Resident Rounds

March 2008

A 12-year-old girl presented to the clinic with a rash she had for two days. Upon further questioning, it was determined the rash originated on her upper back and trunk, and looked like small red papules with a central pustule. The lesions spread to her upper and lower extremities and became pruritic. She has not used any topical or systemic medications to treat the rash.

She denied fevers, cough, rhinorrhea and upper respiratory symptoms, and the remainder of her review of systems is negative. She denied any recent travel, water exposure, animal contact or other sick contacts. She attends junior high school, and one person in her class was sick with chicken pox two weeks previously.

She has a history of Crohn’s disease, and is currently on monthly infliximab infusions and daily methotrexate therapy. She has no other medical problems, no previous surgeries and takes no other medications. Her immunizations were up to date, including varicella vaccination, and she had no history of varicella infection.

Her physical examination was notable for crops of papulovesicular lesions over her trunk, back, face and upper and lower extremities (Figures 1, 2, 3). Some of the lesions were crusted over and others were fluid-filled. The remainder of her examination was normal.

Her laboratory studies showed a peripheral white blood cell count of 9 X 10³/mm³, with 40% neutrophils and 60% lymphocytes. Additionally, she had 250,000 platelets/mm³ and a hematocrit of 37%. Liver transaminases were normal. Blood cultures, a wound culture, viral cultures of various lesions and direct fluorescent antibody (DFA) for herpes simplex virus (HSV) and varicella zoster virus (VZV) were sent on the lesions.

What is your diagnosis?

Answer

The clinical history and characteristic nature of the lesions presented in this case are consistent with primary varicella infection. The patient’s direct fluorescent antibody was positive for varicella-zoster virus and was confirmed by a viral culture. Her wound cultures and blood cultures were negative after five days.

The incubation period of varicella ranges from 10 to 21 days with a mean of 14 days, and symptoms usually are present after 14 to 16 days. Some children experience a prodrome of fever, malaise, anorexia and headache, with the rash appearing within two days. Fever and other constitutional symptoms can be present for up to 72 hours after the start of the rash. The virus is typically transmitted by inhalation of aerosolized respiratory secretions, and has also been reported after direct contact with active skin lesions during acute illness or after varicella vaccination.

The classic rash of varicella, usually described as “dewdrops on a rose petal,” is a vesicular rash that usually starts as crops of fluid-filled vesicles on the scalp, face or trunk, and then spreads to the extremities. The fluid-filled vesicles are surrounded by an erythematous border, and after 24 to 48 hours the lesions begin to crust over and become pruritic.

The rash can be in multiple stages, with some pustular lesions and others crusted over. Occasionally, the mucous membranes can be involved, producing small ulcerative lesions on the conjunctiva or oropharynx. Older age, eczema and preexisting sun trauma can exacerbate lesions at those sites, sometimes resulting in scarring and hypopigmentation.

However, the introduction of varicella vaccine into routine childhood immunizations has modified the clinical presentation in many cases. The rash can appear as an erythematous papular lesion, and be smaller and fewer in number, with some lesions having a central fluid-filled vesicle. The infection usually is attenuated in postvaccination varicella, and often can be difficult to diagnose based on clinical examination findings alone. Therefore, a high index of suspicion and laboratory testing should be performed on any questionable or concerning lesions.

Varicella infection is usually a clinical diagnosis, with the appearance of the characteristic rash and prodromal symptoms. When laboratory confirmation is necessary, rapid antigen detection methods, such as DFA tests, are most commonly used. The sample is taken from a scraping of the base of the lesion.

This patient had a positive DFA for VZV (DFA has higher sensitivity for VZV compared with herpes simplex virus) and was confirmed by viral culture. Antibody titers usually are not present during the incubation period, but start to increase (specifically immunoglobulin M) at the start of the varicella exanthem and can increase by approximately four-fold from baseline levels during acute illness.

IgG levels are not useful in diagnosing acute illness. Despite the presence of antibody titers after acute infection, repeat infection may rarely occur after exposure, and is thought to boost innate immunity to varicella.

One of the major complications and most common causes of morbidity with varicella infection is the development of secondary bacterial infections. The most common organisms are Streptococcus pyogenes (Group A beta-hemolytic streptococci) and Staphylococcus aureus. Infections with these organisms superimposed on a primary varicella exanthem can present as something as simple as impetigo, or as severe as varicella gangrenosa. These severe skin infections can lead to bacteremia, disseminated intravascular coagulopathy or cardiovascular compromise. Other reported complications associated with primary varicella include encephalitis, meningitis, meningoencephalitis and cerebellar ataxia, most of which are associated with rare neurologic sequelae and almost complete resolution of symptoms. Lastly, hepatitis (separate from Reye syndrome), thrombocytopenia, hemorrhagic varicella and purpura fulminans are other rare, yet serious, complications associated with varicella. Some studies have suggested increased incidence of GABHS with use of ibuprofen, and therefore acetaminophen is recommended for fevers.

Adolescents and adult patients who acquire primary infection have a higher morbidity and mortality, usually because of the potential for development of varicella pneumonia, which can lead to pneumonitis and respiratory failure. Another important population of patients in whom varicella can lead to potentially devastating consequences is immunocompromised patients. This includes oncology and transplant patients, individuals with congenital or acquired immunodeficiencies and those on immunosuppressive therapy for chronic diseases (eg, inflammatory bowel disease (IBD), juvenile rheumatoid arthritis). These individuals have a particularly high risk of complications from primary varicella, such as pneumonitis, hepatitis, DIC, purpura, visceral dissemination and encephalitis.

Prompt administration of antiviral therapy is prudent in these patients to prevent rapid progression of disease and fatal outcomes. This patient fell into this category because she had a diagnosis of Crohn’s disease and was currently taking immunosuppressive agents. Infliximab has been reported to be associated with an increased incidence of varicella-zoster infections, mycobacterial infections and cutaneous fungal infections. This patient was taking infliximab and methotrexate for her inflammatory bowel disease and was at a higher risk for disseminated infection.

Treatment for primary varicella in an immunocompetent patient is mainly supportive care and prevention of secondary bacterial skin infections. Treatment with acyclovir is not clinically indicated in healthy children, because the disease is usually self-limited. However, if signs and symptoms of neurologic involvement, pneumonitis or invasive disease are present, acyclovir therapy should be considered. In addition, if underlying medical conditions place the patient at high risk for invasive disease, then intravenous acyclovir should be administered as soon as possible (preferably within the first 72 hours) to prevent progression, and promote earlier resolution of symptoms. Acyclovir therapy is limited by the relative resistance of VZV requiring high doses (80 mg/kg/day) and its poor oral bioavailability. Alternatives include famciclovir and valacyclovir, both of which have higher bioavailability and tolerance, but are not approved for varicella infection or use in young children.

This patient was an immunocompromised child with primary varicella and was at high risk for serious complications. Therefore, she was treated with intravenous acyclovir with close clinical monitoring on the pediatric ward. She continued her intravenous therapy until there were no new lesions and the majority of her initial lesions had crusted over. She did not suffer any complications from her infection, and was discharged after three days.

Varicella-zoster immunoglobulin and VariZIG (Cangene Corporation, Winnipeg, Canada) has been used successfully for prevention of varicella infection in exposed susceptible individuals. It is recommended to begin treatment within 96 hours of exposure to VZV to be effective. It is recommended for use in high-risk populations, such as immunocompromised patients, pregnant women without a history of varicella, neonates born to mothers with active varicella infection during the peripartum period and certain premature infants who are at high-risk. Currently, VZIG is no longer manufactured and VariZIG is available under an investigational drug (IND) protocol. If VariZIG is unavailable, intravenous immunoglobulin (IVIG) can be considered in special circumstances, but there are no recommendations or standards for its routine use in disseminated varicella infection.

This patient presented with a common childhood illness, but in the setting of a slightly complicated medical history. It should be noted that this relatively benign childhood illness can have devastating complications in certain populations and requires prompt recognition and initiation of therapy. Therefore, clinicians need to keep a broad differential and identify risk factors in patients that may predispose them to varicella infection. Accurate identification of varicella infection and initiation of treatment, if clinically indicated, can help prevent dissemination of infection in susceptible individuals.

For more information:

• Anjali Kunz, MD, is a Pediatric Infectious Disease Fellow and a Captain in the U.S. Army. She is affiliated with the USHS. Disseminated primary varicella after initiation of infliximab for Crohn’s disease [letter to the editor]. Am J Gastroenterol. 2004;99:2503-2504.
• Committee on Infectious Diseases, American Academy of Pediatrics, Pickering LK, ed. Red Book, 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.
• Long SS, Pickering LK, Prober CG, Red Book eds. Principals and Practice of Pediatric Infectious Diseases. 2^nd ed. Philadelphia: Elsevier; 2003.
• Tougeron D, Mauillon J, Tranvouez JL. Severe varicella infection during treatment with infliximab for Crohn’s disease. Gastroenterol Clin Biol. 2006;30:1410-1413.