A previously healthy 17-year-old boy presents with a 3-day history of a pruritic maculopapular rash, fever (to 104°F [40°C]), vomiting, and diarrhea to a children’s hospital in the south-central United States during the winter of 2018. These symptoms were preceded by 2 days of nausea, myalgia, and associated dizziness. His rash initially began on the upper chest and neck before progressing to his trunk and extremities.

The patient has a family history of systemic lupus erythematosus (SLE) and was exposed to family members diagnosed as having influenza confirmed by rapid testing. Three days before admission, he was prescribed oseltamivir for presumed influenza, which was discontinued after 2 doses due to concern for drug reaction with the emergence of his rash. The patient and his immediate family deny any recent travel, and he is fully vaccinated. A sexual history was not obtained on admission.

At presentation, he has an 8-lb weight loss during his acute illness and appears ill, with a temperature of 101.6°F (38.6°C), heart rate of 110 beats/min, respiratory rate of 20 breaths/min, and blood pressure of 111/52 mm Hg. On examination he is alert and answering questions appropriately. Cardiac examination reveals tachycardia with regular rhythm but without murmurs, rubs, or gallops. Capillary refill is delayed to 4 seconds, and pulses are 2+ peripherally. Pulmonary and abdominal examination findings are normal, without organomegaly. His rash is deeply erythematous, blanching, and pruritic. Many macules coalesce into a morbilliform eruption that involves his chest and abdomen, with isolated macules along the extremities and left palm (Fig). There is no mucosal involvement or lymphadenopathy.

Figure.

Erythematous macules that are beginning to coalesce into a morbilliform eruption.

Figure.

Erythematous macules that are beginning to coalesce into a morbilliform eruption.

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While in the emergency department, the patient receives 3 normal saline boluses, with improvement in heart rate to 90 beats/min while resting, with a blood pressure of 115/70 mm Hg before admission to the PICU for further management. The initial evaluation includes a negative rapid strep screen, a complete blood cell count that is significant for leukopenia (white blood cell count, 1,990/μL [1.99 × 109/L]), thrombocytopenia (platelet count, 80 × 103/μL [80 × 109/L]), and a notable absence of eosinophilia. He has elevated levels of C-reactive protein (3.7 mg/dL [37 mg/L]) and lactate dehydrogenase (880 U/L [14.7µkat/L]). A complete metabolic panel is normal, and chest radiography shows no abnormalities. A respiratory pathogen panel test for 20 common respiratory viruses, including influenza A and B, was obtained via nasopharyngeal swab, and results are negative before admission. Blood and urine cultures, Epstein-Barr virus titers, and syphilis total antibody are collected and pending at admission. A tickborne antibody panel is sent to evaluate for common pathogens of the region, such as Borrelia, Ehrlichia, and Rickettsia species. He receives doxycycline and clindamycin to cover empirically for tickborne disease or toxin-mediated illness from Staphylococcus aureus or group A streptococcus. After normalization of his heart rate and blood pressure, he is transferred from the PICU to the medical/surgical unit the day after admission.

A comprehensive sexual history is obtained during the transfer of care to the hospitalist service. Our patient reports that his last sexual encounter was 9 months before admission. After a detailed search of encounters in the electronic medical record, an episode of perianal herpes treated 5 months earlier was discovered. Despite this, the patient continues to deny any history of male partners or anal or oral intercourse. Genital and perianal examinations show no signs of rash, lesions, or other concerning findings. A hepatitis panel and human immunodeficiency virus (HIV) testing are obtained after learning of this history.

During the next 36 hours his C-reactive protein level continues to rise, cultures show no growth, and testing from admission begins to return. Syphilis, Epstein-Barr virus, and tickborne panels are all within normal limits, as is his acute hepatitis panel, antistreptolysin O titer, and anti–DNAse B antibody. On hospital day 3, he remains febrile with persistent leukopenia and thrombocytopenia. His morbilliform rash progresses and coalesces such that it involves most of his body, and a fine scale is appreciated that raises concern for erythroderma. The hematology/oncology service is consulted, but bone marrow biopsy was not required because later that day, pending laboratory test results reveal the diagnosis.

The differential diagnosis of a progressive maculopapular rash in the setting of a febrile illness should lead one to consider infectious etiologies. Viral causes such as Epstein-Barr virus, enteroviruses, influenza, and adenoviruses commonly present with fever, rash, and associated gastrointestinal symptoms, as seen in this case. The morbilliform nature of the rash and cephalocaudal progression should raise concern for measles. Evaluation was not performed in our patient given his complete immunization status, negative travel/exposure history, and lack of clinically compatible symptoms such as cough, coryza, and conjunctivitis. Toxin-mediated disease from group A streptococcus and S aureus was considered due the extreme presentation in shock and diffuse rash. Kawasaki disease should also be considered, although this is less commonly seen in patients of his age.

The presence of macules on his palm raises its own set of infectious concerns, such as secondary syphilis and, in particular, Rocky Mountain spotted fever, both of which classically involve the palms and soles. Rocky Mountain spotted fever can present at any time of year in the south-central United States, but it seemed less likely given his presentation during the winter.

Other noninfectious causes of such a rash include DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, but there was a lack of eosinophilia on presentation, and his only known drug exposure was oseltamivir, and the time course is not consistent with DRESS syndrome, which is usually 2 to 8 weeks after exposure. Further differential diagnosis includes autoimmune disorders such as SLE, which was present in his family history. SLE commonly presents on the face in a “butterfly” distribution, although it can be discoid and develop into erythroderma in rare instances. Dermatomyositis or polymyositis could also be considered and can rarely present with generalized erythroderma with myalgia, but noticeably there was no Gottron sign or heliotrope eruption. Given his age it is less likely that this is his first presentation of such a disease, and the myalgia seemed secondary to fatigue and not true weakness.

In cases in which a sexually active patient presents acutely ill with progressive rash and fever, acute retroviral syndrome (ARS) should be considered in the differential diagnosis. If initial diagnostic testing has yielded no explanation, further consideration should be given to acquiring a thorough sexual history and evaluating for ARS.

The results of the patient’s HIV-1/HIV-2 antigen/antibody combination test were positive, leading the laboratory to perform a reflex HIV-1/HIV-2 antibody differentiation assay on the same specimen. Nonreactive antibody results led us to order a plasma HIV RNA (viral load) test for confirmation, but the initial result demonstrated a viral load above the upper limit of the test range. After repeating with a 1:100 dilution, his HIV viral load was calculated to be 61,121,800 copies/mL and confirmed the diagnosis of ARS.

This case represents ARS that presented with shock and progression of morbilliform rash to erythroderma. Characteristically, symptoms occur 1 to 4 weeks after primary infection and are nonspecific but resemble a mononucleosis or flulike illness. Rash is a known presenting symptom that typically begins 2 to 3 days after onset of fever and begins in the upper thorax. It lasts 5 to 8 days and spreads to the face and extremities, occasionally including the palms and soles. Lesions are small, circumscribed, round, pink to deep red macules or papules. (1) Skin manifestations are linked to immune status and the severity of CD4 depletion. In 1 study, 61% of patients with HIV presenting to a dermatology clinic had skin findings. Papular pruritic eruptions were determined to be the most common condition in children and were noted as the hallmark of severe immune suppression. (2) Although severe immune suppression was associated with papular pruritic lesions, it was not associated with opportunistic skin infections. (3)

One of the distinct features of this case is the progression from maculopapular rash to diffuse morbilliform eruption and eventual erythroderma in the course of ARS. There are case reports describing erythroderma in HIV-positive patients, and a study in South Africa by Morar et al (4) compared erythroderma in HIV-positive and HIV-negative patients. They evaluated patients with a diagnosis of erythroderma and then tested for HIV status in that population. Of patients presenting with erythroderma, 43% were found to be HIV positive. Across all patients, preexisting dermatoses (psoriasis, dermatitis, pityriasis) accounted for almost 65% of all erythroderma, with a similar description to the papular pruritic eruption mentioned previously herein. In comparing the 2 groups, drug reactions (specifically to ethambutol and isoniazid) were most commonly the cause in HIV-positive patients (40.6%). Fever and lymphadenopathy were more prevalent in HIV-positive patients, and mortality increased from 5% (if HIV negative) to 10% (in HIV-positive patients). The conclusion was that erythroderma in children may suggest HIV infection, and, consequently, HIV positivity is a risk factor for developing erythroderma. (4)

The diagnosis in this case was delayed due to difficulty in obtaining an accurate sexual history. A recent study by Liddon et al (5) found that many young patients (88%) disclose their sexual history to their providers, but younger patients (ages 14–17 years) are significantly less likely to compared with 18- to 24-year-old patients (25.4% vs 3.9%). Positive patient-provider relationships were cited as encouraging truthful disclosures. (5) However, it can take time for those relationships to develop, and building that trust in cases of acute illness and/or where an intensive level of care is required presents additional challenges.

After confirmation of the diagnosis, genotyping was performed to examine for resistance using the curated Stanford University HIV-1 Drug Resistance Database. Our patient was started immediately on antiretroviral treatment. Fever, rash, nausea, and myalgia resolved, and he was discharged with close outpatient follow-up.

After discharge, HIV genotyping results showed no resistance, and a CD4/CD8 panel demonstrated improved CD4 count and helper/suppressor ratio, with a viral load of 74 copies/mL. Efforts were made to obtain a more complete history after the HIV diagnosis, but the patient continued to deny any at-risk sexual behavior, male partners, or sexual abuse. Because of this, confidential partner notification through the health department for testing was unable to be performed.

Summary

  • Human immunodeficiency virus has many presentations, and acute retroviral syndrome can mimic mononucleosis or a flulike illness, with symptoms developing 1 to 4 weeks from the initial infection. (1)

  • One should remain suspicious for acute retroviral syndrome in the acutely ill child/adolescent with a morbilliform rash progressing to erythroderma and concern for viral illness unexplained by initial diagnostic testing.

  • Acute retroviral syndrome should be considered even when no risk factors have been elicited because it can take time for patients to build enough trust to disclose sensitive sexual history.

  • A thorough social and sexual history is a critical component of the initial interview with all adolescents, and further transitions of care or consultations offer a unique opportunity to confirm and continue to gather important components of the patient’s presentation. Providers should not rely on hearsay or previous accounts of the patient’s history.

AUTHOR DISCLOSURE:

Drs Harris and Schwenk have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.

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