17-year-old patient with fever and rash

Issue: April 2010

A 17-year-old male patient presented to the outpatient clinic with fever and a rash.

The rash had started five days ago on his lower leg and he had been seen in an emergency room.

He was told it was a bite and placed on oral clindamycin. Subsequently the rash progressed to involve all his extremities. He was unable to walk and came to the clinic in a wheelchair. On review of systems, he also complained of chills and joint pains. On further questioning about unusual exposures he stated that he had been in a fight before the rash began and had fallen in the grass. His past medical history was remarkable for some risky behaviors including cigarette smoking, alcohol ingestion and sexual activity. He had also been diagnosed with attention-deficit/hyperactivity disorder (ADHD) a few years ago but was not on any ADHD medications at present.


The patient had multiple large, raised, extremely tender, erythematous lesions on the hands, forearms and upper arm. Photos courtesy of Sabiha Hussain	The patient had similar lesions on the extensor aspects of his lower legs extending up to the middle of his thighs.	The patient had multiple large, raised, extremely tender, erythematous lesions on the hands, forearms and upper arm.

On examination, the patient was alert and interactive. He was wheelchair bound. He had a temperature of 101.3° F, pulse of 88 beats/min, respiratory rate of 16 breaths/min. Blood pressure could not be obtained as he complained of arm pain. His weight was 203 pounds. He was noted to have multiple large, raised, extremely tender, erythematous lesions on the hands, forearms and upper arms (Figure 1 and Figure 3) and similar lesions on the extensor aspects of his lower legs extending up to the middle of his thighs (Figure 2).The rest of his examination was within normal limits. The patient was sent to the emergency room.

Labs done were remarkable for a white blood cell count of 17,600/mm³ with 83.7% neutrophils. Comprehensive metabolic panel was significant for sodium of 130 and an AST of 44 and ALT of 91. A chest x-ray was normal. The patient was given a bolus of normal saline and he was discharged home with a prescription for a medication that he was advised to start empirically. An additional laboratory test revealed the diagnosis.

What’s your diagnosis?

The patient’s non-quantitative coccidioidomycosis IgM and IgG tests were positive. He was diagnosed with erythema nodosum and coccidioidomycosis.

The patient followed up in the emergency room two days later. He had not started fluconazole that was prescribed empirically as it was not covered by his insurance. He was given a prescription for itraconazole and advised to follow up with his primary care doctor. The patient followed up in our clinic two days later. He had started taking the fluconazole two days earlier, was feeling better and the rash was significantly improved. Labs were done on the same day. His white blood cell count was now 13,400/mm³, AST was 94 and ALT was 247. Coccidioidomycosis titers were 1:4. The patient was advised to discontinue the fluconazole immediately and go to the emergency room for admission. The patient was admitted for three days and had daily monitoring of LFTs. The erythrocyte sedimentation rate on admission was >100 and coccidioidomycosis IgG titer was 1:8. His ALT peaked at 307 and AST peaked at 114 on the second day of admission. He was not placed on any antifungal medications during the hospital stay or on discharge. On the day of discharge his ALT was 289 and AST was 103.

The patient followed up in the clinic four days after hospital discharge. The rash had completely resolved and he was afebrile and feeling much better. Repeat labs done four days later showed a white blood cell count of 6200/mm³, an AST of 93 and an ALT of 194. The erythrocyte sedimentation rate was 25 mm/hr.

Coccidioidomycosis is caused by soil fungi of the genus Coccidioides, a dimorphic fungus that usually grows as a mold. This fungus occurs naturally only in the Western Hemisphere, primarily in the southwestern United States and Mexico.

Areas of hyperendemicity include Kern, Tulare, and Fresno counties in the San Joaquin Valley of California and Pima, Panal, and Maricopa counties in Arizona. Major cities in these areas include Bakersfield in California and Phoenix and Tucson in Arizona. Coccidioidomycosis has been termed a “great imitator” disease and has diverse manifestations, generally sparing only the eyes and gastrointestinal tract. A diversity of cutaneous manifestations have been associated with coccidioidomycosis. Two general types of cutaneous disease exist: reactive skin lesions secondary to infection elsewhere (usually in the lungs) and lesions caused by dissemination of the fungus to the skin. Reactive lesions include toxic erythema, erythema nodosum and erythema multiforme. Primary cutaneous infection is extremely rare, presenting in 1-2% of all cases.

Erythema nodosum consists of the sudden appearance of very tender, erythematous nodules 1 to 10 cm in diameter usually located symmetrically on the extensor surface of the legs. Lesions can also develop elsewhere including the calves, thighs, trunk, upper extremities, head and neck. Erythema nodosum occurs one to three weeks after the onset of illness. Histologically, septal granulomatous panniculitis is observed. It is a marker of the onset of a robust cell-mediated immune response and is associated with a favorable prognosis. The triad of erythema nodosum, fever and respiratory illness associated with coccidioidomycosis is known as valley fever. Erythema nodosum in children has a much shorter duration than in adults, arthralgias are seen in a minority of patients, and fever is an accompanying manifestation in fewer than half of the cases.

Differential diagnosis of erythema nodosum includes insect bite hypersensitivity reaction, lupus panniculitis, factitial panniculitis, superficial thrombophlebitis, polyarteritis nodosa, necrobiosis lipoidica diabeticorum, erythema induratum, erythema nodosum leprosum and sarcoidosis.

Erythema nodosum in children in the United States is most commonly associated with group A streptococcal pharyngitis. Other associated infectious agents include tuberculosis (worldwide), coccidioidomycosis (in the southwestern United States), Yersinia enterocolitica (in Europe), cat-scratch disease (Bartonella henselae), and tularemia. Erythema nodosum can also be associated with: (1) use of drugs, such as sulfonamides and oral contraceptive agents; (2) sarcoidosis and, occasionally, malignancies such as leukemia and lymphoma; and (3) systemic diseases, including Behcet disease, Reiter disease, systemic lupus erythematosus and inflammatory bowel disease.

The main difficulty in diagnosis is failure to consider coccidioidomycosis and the diagnosis is often delayed because the infection is not considered initially. The diagnosis is best established using serologic, histopathologic and culture methods. Serologic tests are useful to confirm diagnosis and provide prognostic information. An IgM response is detectable one to three weeks after symptoms appear and can be detected in up to 75% of patients with primary disease, three to four months after onset. IgG titers usually are low and transient if the disease is asymptomatic and mild. Persistent high IgG titers (1:32 or greater) occur with severe disease and almost always in disseminated infection. Antifungal therapy generally is not indicated for uncomplicated primary infection. However, some experts would consider a treatment course with fluconazole or itraconazole for people who are experiencing significant morbidity as evidenced by prolonged duration of symptoms of more than three weeks, weight loss of greater than 10%, marked chest pain, or severe malaise. Treatment is indicated for all extrapulmonary manifestations of coccidioidomycosis.

This case was unusual in a number of ways.

The distribution of the rash was not typical of erythema nodosum, the patient presented with more adult than pediatric type features of erythema nodosum and his liver function tests at baseline were elevated. His liver function tests also rose very rapidly after starting fluconazole treatment limiting treatment options.

Furthermore, he was misdiagnosed at initial presentation despite residing in the San Joaquin Valley where clinicians have a higher index of suspicion for the diagnosis due to the hyperendemicity of coccidoidomycosis in this region. This case highlights the importance of keeping local epidemiology in mind even in the face of unusual clinical presentations. Timely diagnosis of coccidoiodomycosis can significantly reduce morbidity and health care costs and can potentially be life-saving.

Sabiha Hussain MD, works with the Department of Pediatrics, Family Health Center/Community Action Partnership of Kern.

For more information:

Anstead GM, Cadena-Zuluaga J. Coccidioidomycosis: Recognizing the varied clinical presentations. Infs in Med. 2009; 26: 198-210.

Jaramillo-Moreno G. Primary cutaneous coccidiodomycosis: case report and review of the literature. Int J of Derm. 2006; 45: 121-123.

Long S, Pickering L, Prober C. Principles and Practice of Pediatric Infectious Diseases. 3rd ed. 2008 Elseiver Inc.

Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book. Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, Il: American Academy of Pediatrics; 2009 .

Requena L, SanchezYus E. Erythema nodosum. Dermatol Clin. 26 (2008) 425-438 .

Stevens D. Current concepts. Coccidioidomycosis. NEJM. 1995; 332: 1077-1082.