Christine Chang, MD

A 3-week-old infant with vesicular eruptions receives a diagnosis of varicella requiring hospitalization and intravenous acyclovir.

A 3-week-old previously healthy full term girl presented to the pediatric emergency department with 2 lesions on the body that had developed 3 days earlier—1 lesion on the forehead and 1 perianal lesion. Her parents said that she had recently developed mild nasal congestion and fussiness but denied fever, purulent drainage, bleeding from the lesions, or rashes elsewhere. The infant had been feeding well with appropriate urine output for age. Her mother had a history of genital warts, but neither parent had a history of oral or genital herpes simplex virus (HSV) infection. The patient presented to her pediatrician earlier that day and after evaluation, given her young age, she was referred to the emergency department for work-up of a possible HSV infection.

In the pediatric emergency department, the infant appeared well. Her temperature was 37.3° C, heart rate was 156 beats per minute, respiratory rate was 33 breaths per minute, and her oxygen saturation level was 100% on room air. She weighed 3.3 kilograms. Physical examination was significant for a ruptured 3-mm vesicle with a central crust on the medial aspect of the right eyebrow (Figure 1) with some tiny pustules and scattered erythema and scale on the forehead, nasal bridge, and eyelids with the right side lesions more prominent than the left. She also had a 3-mm crust with a narrow scaly border and surrounding erythema on the right buttock (Figure 2). Her parents brought a photo of the right eyebrow lesion from 2 days before it ruptured that showed a 4-mm intact vesicle with a narrow rim of erythema (Figure 3). The patient had normal tone, normal strength, and open, flat anterior and posterior fontanelles. There was no appreciable hepatosplenomegaly, lymphadenopathy, or rash noted elsewhere.

Given her age and presentation, HSV infection was the leading and most concerning diagnosis in the differential diagnosis, but varicella and staphylococcal infections were also considered. A differential diagnosis for vesicular lesions in infants is shown on Table 1 and includes infectious etiologies and well as congenital and neonatal bullous disorders.

A complete neonatal sepsis rule-out was performed given the infant’s age. Laboratory studies revealed an unremarkable complete blood cell count in addition to differential, comprehensive metabolic panel, C-reactive protein, procalcitonin, and urinalysis. A lumbar puncture produced blood-tinged fluid on the second attempt, and initial cerebrospinal fluid (CSF) studies showed 416 white blood cells per microliter and 605,000 red blood cells per microliter, with 4% neutrophils, 83% lymphocytes, 1% reactive lymphocytes, and 12% monocytoid cells. The laboratory was unable to run protein and glucose studies on the CSF. No organisms were seen on CSF Gram stain. Cultures from blood, urine, and CSF were sent in addition to multiplex polymerase chain reaction (PCR) testing with a respiratory pathogen PCR panel from the nasopharynx and a CSF meningitis/encephalitis panel. The patient was started on empiric intravenous ampicillin, gentamicin, and acyclovir and admitted to the neonatal intensive care unit (NICU) for further treatment.

Shortly after admission, the infant’s CSF meningitis/encephalitis panel resulted positive for varicella-zoster virus (VZV) and her respiratory pathogen PCR panel resulted positive for coronavirus (not SARS-CoV-2). Pediatric infectious diseases (ID) was consulted, given the presence of varicella infection in a newborn with no clear history of exposure. The ID consult recommended HSV and VZV PCR tests from the patient’s blood, CSF, and a skin lesion, as well as HSV PCR tests from her conjunctiva, nares, oropharynx, and rectum. All HSV PCR tests resulted negative. Notably, the patient’s PCR test results were positive for VZV in the skin lesion and blood but not in the CSF. As the CSF VZV PCR test was negative, the VZV result from the CSF meningitis/encephalitis panel was thought to be representative of sampling from the blood introduced from the traumatic lumbar puncture. Nevertheless, the infant was found to have positive VZV PCR testing from multiple sources (ie, skin lesion, blood).

Varicella, commonly known as chickenpox, is caused by a primary VZV infection. It most often affects children unimmunized against the disease, with the highest incidence in children aged between 1 and 9 years.

 It usually results in mild to moderate illness in otherwise healthy individuals, but tends to be more severe in infants, teenagers, and adults compared with school-aged children.

 Some presentations of varicella can be severe and life-threatening, especially in cases of vertical transmission (ie, either fetal infection after the development of maternal varicella or neonatal infection around the time of delivery) and in immunocompromised individuals.

 Possible complications include bacterial superinfection of skin lesions, pneumonia, and central nervous system involvement.

 The risk of hospital admission or dying from varicella in infants is higher than that in children.

Varicella presents with a pruritic rash with vesicles in different stages of development, often accompanied by fever, malaise, and decreased appetite.

 The rash tends to be more prominent on the face and trunk than on the extremities.

 VZV is transmitted via airborne droplets or vesicular fluid.

 It is thought to multiply in regional lymph nodes, then to spread to the viscera.

 The incubation period for varicella varies between 10 to 21 days. Individuals with varicella are contagious from 1 to 2 days before the onset of rash until all of the lesions have crusted over, which is typically at least 5 days after the onset of rash.

Varicella can be diagnosed clinically by the presentation of a characteristic rash. In cases that require laboratory confirmation, the diagnostic method of choice for varicella is a VZV DNA PCR test from vesicular fluid or a scab—vesicles contain large amounts of virus and PCR is more sensitive than a viral culture or a direct fluorescent antibody assay.

In otherwise healthy children, treatment for varicella is supportive care to address fever and pruritus and to maintain adequate hydration.

 Varicella in a newborn does not universally require antiviral treatment, and there is no consensus by experts in the literature about management.

 However, the decision to treat is determined by host characteristics, illness severity, and initial response to therapy.

 The antiviral treatment of choice is acyclovir, which prevents viral DNA synthesis by inhibiting the viral DNA polymerase and is most effective if administered intravenously within 72 hours of disease.

 Blumental et al recently recommended acyclovir treatment for all patients less than 1 month of age with clinical signs of varicella.

Both of the infant’s parents reported having a childhood illness consistent with varicella and tested positive for VZV immunoglobulin G. As the patient’s mother tested positive, it is likely that maternal transfer of antibody contributed to a less severe course of varicella (though this is confounded by the fact that the infant was started empirically on intravenous acyclovir upon admission).

 Given varicella’s incubation period, we presume the patient was exposed to VZV during the first week of life. Though no clear source of infection was ultimately identified, it is most likely that the infant was exposed in her pediatric clinic, as she was seen in clinic on days of life 3, 5, 6, and 14 for weight and jaundice checks and a routine 2-week well care visit.

The day after admission, the infant developed additional vesicular lesions on her trunk and extremities. Given the patient’s positive CSF meningitis/encephalitis panel—despite the history of a traumatic lumbar puncture and the negative dedicated VZV PCR from the CSF—ID recommended a plan to treat for at least 7 days while continuing to monitor the infant. Intravenous acyclovir was continued, but antibiotics were discontinued by 48 hours as there was less concern for bacterial infection and negative cultures. Amplitude-integrated electroencephalography was unremarkable. The patient had 1 isolated temperature to 38.0°C that resolved without medication. She was continued on intravenous acyclovir for 1 week until hospital discharge. At that time, all cultures were negative for bacterial infection and the infant’s vesicular lesions had scabbed over.

This case highlights the importance of providers including varicella in the differential diagnosis of vesicular lesions in infants, as often its consideration is overshadowed by the concern for possible HSV. Continuing to administer routine varicella vaccinations is also important from a public health perspective, in order to maintain herd immunity in populations.

. 2006;368(9544):1365-1376. doi:10.1016/S0140-6736(06)69561-5

2. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. 

3. Kennedy PGE, Gershon AA. Clinical Features of Varicella-Zoster Virus Infection. 

4. Meyer PA, Seward JF, Jumaan AO, Wharton M. Varicella mortality: Trends before vaccine licensure in the United States, 1970-1994. 

. 2000;182(2):383-390. doi:10.1086/315714

Red Book: 2018 Report of the Committee on Infectious Diseases. 

31st ed. Itasca, IL: American Academy of Pediatrics; 2018:869-883.

6. Sauerbrei A, Wutzler P. Neonatal varicella. 

. 2001;21(8):545-549. doi:10.1038/sj.jp.7210599

7. Blumental S, Lepage P. Management of varicella in neonates and infants. 

. 2019;3(1):e000433-2019-000433. eCollection 2019. doi:10.1136/bmjpo-2019-000433

8. Galil K, Brown C, Lin F, Seward J. Hospitalizations for varicella in the United States, 1988 to 1999. 

. 2002;21(10):931-935. doi:10.1097/00006454-200210000-00009

9. Lecuyer A, Levy C, Gaudelus J, et al. Hospitalization of newborns and young infants for chickenpox in France. 

. 2010;169(10):1293-1297. doi:10.1007/s00431-010-1212-9

10. Gowin E, Wysocki J, Michalak M, Januszkiewicz-Lewandowska D. Too young to be vaccinated: Hospitalizations caused by varicella among children in the first year of life. 

. 2017;62:52-55. doi:10.1016/j.ijid.2017.07.009

11. Sauerbrei A. Diagnosis, antiviral therapy, and prophylaxis of varicella-zoster virus infections. 

. 2016;35(5):723-734. doi:10.1007/s10096-016-2605-0

12. Whitley RJ. The use of antiviral drugs during the neonatal period. 

. 2012;39(1):69-81. doi:10.1016/j.clp.2011.12.004

Articles

A 3-week old girl comes to an emergency room with vesicular eruptions and recent mild nasal congestion and fussiness. What’s the diagnosis?

A 3-week-old girl with vesicular rash

A 5-month-old previously healthy, full-term female presented to a pediatric emergency department (ED) with 2 weeks of left leg swelling. Her parents denied any history of trauma, pain, fevers, weight loss, and easy bruising or bleeding, and family history was negative for cancer. The patient had been feeding and eliminating well. The parents said that x-rays of the patient’s left leg were obtained at a different ED soon after they had noted the sudden-onset swelling. At the time they were told that the x-rays were abnormal, and they decided to report to the pediatric ED because authorization for an outpatient magnetic resonance imaging (MRI) study ordered by the patient’s primary pediatrician was taking too long.

In the pediatric ED, the patient was well appearing. Her temperature was 98.42°F; heart rate was 164 beats per minute; respiratory rate was 28 breaths per minute; blood pressure was 127/68 mm Hg (although she was moving while the measurement was obtained); and her oxygen saturation level was 99% on room air. She weighed 6.8 kg.

Physical examination showed significant swelling below the patient’s left knee without erythema, warmth, or apparent tenderness. The infant had intact pulses, no lymphadenopathy, no hepatosplenomegaly, no rash, and no swelling noted elsewhere. She moved all extremities equally with normal range of motion and strength.

Laboratory studies revealed an elevated white blood cell count (20.15 K/uL) as well as an elevated platelet count (722 K/uL) and elevated inflammatory markers (C-reactive protein, 5.0 mg/dL; erythrocyte sedimentation rate, 44 mm/h). A comprehensive chemistry panel, lactate dehydrogenase, and uric acid were unremarkable. Additionally, x-rays of the patient’s left lower extremity and chest were obtained, which preliminarily showed marked periosteal reaction involving the left tibia and fibula and multiple ribs on the left (Figures 1A and 1B).

The differential diagnosis in the ED included trauma, osteomyelitis, and malignancy (Table). Other conditions on the differential for unilateral lower extremity soft tissue swelling can be ruled out by the patient’s age of presentation, other associated symptoms, and pattern of bone involvement.

Primary bone malignancies such as osteosarcoma and Ewing sarcoma are very rare in infants. Benign bone and soft tissue tumors such as chondroblastomas and osteoid osteomas do not typically present with marked periosteal reaction in multiple areas. Vitamin deficiencies such as scurvy and rickets are not self-limiting and typically present with other clinical findings (eg, petechiae, corkscrew hairs, and gum disease in scurvy). Exposure to medications such as prostaglandin E (eg, in infants with cyanotic congenital heart disease) and vitamin A can be obtained on history.

 Prostaglandin E is thought to promote osteogenesis by decreasing bone resorption and vitamin A is thought to regulate osteoblasts and osteoclasts. Accidental and nonaccidental trauma should be ruled out with careful history taking and scrutiny of the distribution of bone involvement.

 Other important diagnoses to include in the differential are infection (eg, osteomyelitis), endocrine disorders, and rare metabolic disorders.

The Orthopedic Surgery and Oncology services were consulted due to a strong concern for malignancy. A skeletal survey was obtained (Figures 2A and 2B), and the patient was admitted to the Oncology Service for further management, with the tentative plan by Oncology to obtain an MRI of the left leg and a computed tomography (CT) scan of the chest the following morning.

Upon further review of the patient’s x-rays and skeletal survey, multiple specialists-including pediatric radiologists-agreed that the imaging showed marked cortical hyperostosis of the mandible, ribs, and left tibia and fibula-diagnostic of Caffey disease.

Caffey disease (also known as infantile cortical hyperostosis, Caffey-Silverman syndrome, or Smyth syndrome) is a rare, self-limiting condition that should be included in the differential diagnosis of soft tissue swelling in infants. It presents in approximately 3 per 1000 infants prior to 6 months of age, although this is thought to be an underestimation due to underdiagnosis. The condition affects males and females equally and has no ethnic predilection.

 It is usually characterized by irritability, soft tissue swelling, and cortical bone thickening; however, irritability was not seen in this patient.

Delayed diagnosis may occur because the disorder can present with nonspecific symptoms such as fever, fussiness, and decreased appetite, and therefore can mimic other diagnoses, such as malignancy, trauma, and infection. Swelling usually occurs suddenly and may be red, firm, and/or tender.

 Laboratory tests may reveal leukocytosis, thrombocytosis, and/or elevated inflammatory markers, all of which were noted in this patient.

The etiology of Caffey disease is unclear, but it is thought to be a type I collagenopathy. Both sporadic and familial forms occur. The mandible is the most likely affected bone in sporadic cases, whereas the tibia is most likely affected in familial cases. Autosomal dominant and autosomal recessive patterns of inheritance have been reported by reviewing pedigrees of unrelated families.

In families with autosomal dominant inheritance, a missense mutation has been found in 

, which codes for the alpha 1 chain of type I collagen.

 Interestingly, other reported mutations that affect the synthesis of type I collagen include osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome. It is unclear why a missense mutation would stimulate hyperostosis, and it is also unclear why this mutation would affect individuals at a specific age.

The autosomal recessive pattern is distinct from the classic presentation of Caffey disease in that it is associated with prenatal onset and has a much more severe course (eg, angulations and shortness of long bones, polyhydramnios, and fetal hydrops, in addition to marked hyperostosis) and a poorer prognosis.

With good clinical suspicion and multidisciplinary input, early identification of Caffey disease can prevent unnecessary workup and invasive procedures. Diagnosis is made by physical exam and radiographic findings. Although imaging may be variable during the clinical course, the classic finding is cortical diaphyseal periosteal new bone formation. Usually x-ray suffices to clinch the diagnosis; however, MRI could add additional value in diagnosis if infection or malignancy is high on the differential or if there is a question of subperiosteal hemorrhage.

Because Caffey disease doesn’t affect epiphyses or metaphyses, growth potential should not be affected. The pattern of bone involvement is usually multifocal and asymmetric.

 Involved bones typically include the mandible, clavicles, ribs, and long bones. The involvement of the mandible-the most frequently affected bone-is usually pathognomonic and affected in 70% to 90% of cases.

 With mandibular involvement, infants may refuse to eat, leading to failure to thrive.

Caffey disease usually resolves within 6 to 12 months. Treatment typically consists of nonsteroidal anti-inflammatory drugs (NSAIDs) as needed. The use of steroids has been proposed to accelerate bone remodeling and may be trialed if there is a poor response to NSAIDs. In rare cases, Caffey disease can cause enough long-term bony deformity (eg, excessive hyperostosis leading to fusion of adjacent bones) that surgical correction is needed. Other complications include exophthalmos, pleuritis, and recurrence of disease.

For this patient, no additional imaging was obtained, and she did not require any medical or surgical intervention. She was discharged home with plans to follow up with Orthopedic Surgery. Serial x-rays obtained during outpatient clinic visits with Orthopedic Surgery demonstrated interval bone remodeling (Figures 3A, 3B, 3C), with marked improvement and minimal residual deformity noted 10 months after discharge.

1. Menashe SJ, Iyer RS, Parisi MT, Otto RK, Stanescu AL. Pediatric chest radiographs: common and less common errors. 

2. Velaphi S, Cilliers A, Beckh-Arnold E, Mokhachane M, Mphahlele R, Pettifor J. Cortical hyperostosis in an infant on prolonged prostaglandin infusion: case report and literature review. 

3. Woo K, Emery J, Peabody J. Cortical hyperostosis: a complication of prolonged prostaglandin infusion in infants awaiting cardiac transplantation. 

4. Christian CW, States LJ. Medical mimics of child abuse. 

5. Prior AR, Moldovan O, Azevedo A, Moniz C. Caffey disease in neonatal period: the importance of the family! 

6. Glorieux FH. Caffey disease: an unlikely collagenopathy. 

7. Kamoun-Goldrat A, le Merrer M. Infantile cortical hyperostosis (Caffey disease): a review. 

8. Shandilya R, Gadre KS, Sharma J, Joshi P. Infantile cortical hyperostosis (Caffey disease): a case report and review of the literature--where are we after 70 years? 

9. Barba WP, Freriks DJ. The familial occurrence of infantile cortical hyperostosis in utero. 

10. Gensure RC, Makitie O, Barclay C, et al. A novel 

 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. 

11. Schweiger S, Chaoui R, Tennstedt C, Lehmann K, Mundlos S, Tinschert S. Antenatal onset of cortical hyperostosis (Caffey disease): case report and review. 

12. Sanders DG, Weijers RE. MRI findings in Caffey's disease. 

A 5-month-old previously healthy, full-term female presented to a pediatric emergency department with 2 weeks of left leg swelling. Her parents denied any history of trauma, pain, fevers, weight loss, and easy bruising or bleeding, and family history was negative for cancer. The patient had been feeding and eliminating well.

Christine Chang, MD

Articles

A 3-week-old girl with vesicular rash

Infant’s leg swelling could be malignancy