12-year-old boy admitted for febrile illness

edited by Michael Rajnik, MD

A previously healthy 12-year-old boy is admitted to the inpatient ward in mid-July for evaluation of a febrile illness. He had a rapid onset of fever beginning eight days prior to admission with temperatures typically around 102ºF, although as high as 105ºF. In addition to persistent fever, myalgias and general malaise, the patient complains of a severe frontal headache and nonspecific abdominal pain. Three days ago he developed a nonpruritic erythematous rash on his trunk with gradual spread to his bilateral upper and lower extremities.

The patient denies visual changes, neck pain or vertigo. He has had no diarrhea, but has had several episodes of nonbloody, nonbilious emesis over the past two days. Review of systems is negative for cough, congestion, rhinorrhea, pharyngitis, night sweats, anorexia and weight loss.

His past medical history is remarkable only for attention deficit disorder treated with dextroamphetamine. His immunization status is appropriate for his age and he has no reported medication allergies.

The patient lives with his parents and four siblings in Maryland. His home is located in a wooded area with deer and rabbits often spotted in the backyard. The family has no pets. His only recent travel was to a Maryland beach resort two weeks ago.

On examination, he had a temperature of 102.9ºF, heart rate of 88 beats per minute, respiratory rate of 20 breaths per minute, blood pressure of 95/50, and oxygen saturation of 99% on room air. He was ill appearing although awake and appropriate throughout the examination. His oropharynx was nonerythematous without exudates. No oral lesions were visualized. He had full range of motion in his neck without pain. There was no cervical, axillary or inguinal lymphadenopathy.

On cardiac auscultation, the patient had a soft systolic murmur at the left sternal border with normal rate and rhythm. Respiratory exam was clear without wheezes or crackles. He had normoactive bowel sounds with mild tenderness to palpation of the abdomen throughout all quadrants. Hepatosplenomegaly was not present. He had a faint macular rash present on his trunk and bilateral upper and lower extremities with sparing of the palms and soles. Musculoskeletal exam revealed no abnormalities.

Initial laboratory work-up included a complete blood count, erythrocyte sedimentation rate, C-reactive protein, complete metabolic panel and blood culture. The results were significant for leukopenia (WBC=1300), thrombocytopenia (platelets=3200) and hyponatremia (Na⁺=126). In addition, he had an elevated C-reactive protein and elevated transaminases (AST=168, ALT=103).

What illnesses are at the top of your differential diagnosis based on this patient’s presentation, exam and laboratory findings? What treatments do you want to initiate?

Rickettsial illness was suspected in this patient with fever, myalgias, rash and headache in the face of leukopenia, thrombocytopenia and hyponatremia. Both human ehrlichiosis and Rocky Mountain spotted fever were a concern in this patient. Doxycycline was started empirically. A peripheral blood smear was examined for the presence of morulae and serologies were sent for the rickettsial illnesses of concern.

After 48 hours of doxycycline therapy, the patient defervesced with gradual improvement in his clinical status. He was discharged home after three days with plans to complete a seven-day course of doxycycline. Initial serologies done as an inpatient were negative for Rickettsia rickettsii, Ehrlichia chaffeensis, Ehrlichia ewingii and Anaplasma phagocytophilum. However, convalescent serologies drawn four weeks after discharge were positive for E. chaffeensis with titers of 1:512 for IgG and 1:160 for IgM.

Ehrlichiosis

The organisms that cause ehrlichiosis are all members of the family Rickettsiaceae with five different species responsible for human disease. Three of these are found in the United States: Ehrlichia chaffeensis, Anaplasma phagocytophilum (formerly Ehrlichia phagocytophila) and Ehrlichia ewingii. All are gram-negative cocci and obligate intracellular bacteria. E. chaffeensis targets macrophages, causing monocytic ehrlichiosis, while A. phagocyophilum and E. ewingii target granulocytes and lead to granulocytic ehrlichiosis. Typically, infections with E. chaffeensis are the most severe of the ehrlichioses.

In the United States, E. chaffeensis and E. ewingii infections occur predominantly in the southeast, south central and midwest states. They are most commonly transmitted via the Lone Star tick (Amblyomma americanum). A. phagocyophilum infections typically occur in the northeastern and north central states as well as northern California. The most common tick vectors for these bacteria include the black-legged/deer tick (Ixodes scapularis) and the western black-legged tick (Ixodes pacificus). Ixodes ticks can also transmit babesiosis and Lyme disease, and there have been reports of dual infection.

Since its initial description in 1987, most cases of symptomatic ehrlichiosis have been in adults. This is in sharp contrast to other tickborne illnesses, which are more common in the pediatric population. However, recent seroprevalence studies suggest E. chaffeensis infections are common in children. Most infections occur between April and September with peak occurrence from May to July. The incubation period for human ehrlichiosis is typically five to 10 days after the tick bite.

Clinical manifestations of ehrlichiosis are broad and nonspecific. Common complaints in children include fever, myalgia and headache. Additionally, chills, malaise, arthralgia, nausea, vomiting, anorexia and acute weight loss may be reported. Diarrhea, abdominal pain, cough or mental status changes occur less frequently.

The clinical appearance of a rash is variable. Pediatric patients with E. chaffeensis are more likely to have a rash than affected adults (66% vs. 25% in reports). However, only a small percentage (less than 5%) of all patients with A. phagocytophilum infection exhibit a rash. If present, the rash involves the trunk with sparing of the palms and soles (in contrast to Rocky Mountain spotted fever) and is maculopapular, macular or papular.

In severe cases, pulmonary infiltrates, bone marrow hypoplasia, respiratory failure, encephalopathy, meningitis, DIC, spontaneous hemorrhage and renal failure can be seen. The vasculitis and endothelial damage characteristic of other rickettsial diseases does not occur in ehrlichiosis. Symptoms usually resolve by two weeks without sequelae, although secondary or opportunistic infections can occur in severe disease.

Laboratory findings are similar to those found with other rickettsial disease. Leukopenia, thrombocytopenia and elevated transaminase levels are characteristic of early disease. Lymphocytopenia and neutropenia may both be observed. Anemia, hyponatremia and cerebral spinal fluid abnormalities (CSF) (pleocytosis with a predominance of lymphocytes and elevated protein) are also common.

Diagnosis and treatment

Diagnostic testing available for ehrlichiosis includes indirect immuofluorescence assays for specific IgG or IgM, PCR amplification assays, morulae visualization and organism isolation.

As with other rickettsial illness, treatment should be started based on clinical diagnosis without awaiting laboratory confirmation. Doxycycline (4.4 mg/kg/day divided twice daily; maximum 100 mg/dose) is the drug of choice for the treatment of human ehrlichioses. It can be given intravenously or orally. Failure to respond to therapy within the first three days suggests an agent other than E. chaffeensis, A. phagocytophilum or E. ewingii.

While there are concerns regarding dental staining with tetracyclines, doxycycline courses of 14 days or less do not cause significant discoloration of permanent teeth. Treatment course should continue for at least three days after defervescence for a minimum of five to 10 days. Severe or complicated disease may require longer treatment courses. Other broad-spectrum antibiotics, including penicillins, cephalosporins, aminoglycosides and macrolides are not effective.

Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.

Ashley M. Maranich, MD, is a Captain in the U.S. Army. She is currently an Assistant Professor of Pediatrics and a Pediatric Infectious Disease Fellow at the F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences in Bethesda, Md.

Rajesh Daniels, MD, is a Captain in the U.S. Army. He is currently a Resident in Pediatrics with the National Capital Consortium in Washington, D.C., and Bethesda, Md.

Michael Rajnik, MD, is a Lieutenant Colonel in the U.S. Air Force. He is currently the Pediatric Infectious Disease Fellowship Director and Assistant Professor of Pediatrics at the F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences in Bethesda, Md.

For more information:

• Clin Pediatr. 2007;46(2):121-6.
• Infect Dis J. 1998;17(5):429-31.
• Long S, Pickering L, Prober C, editors. Chapter 170: Ehrlichia and Anaplasma species. Principles and Practice of Pediatric Infectious Disease. 3rd ed: Elsevier Science; 2008
• Red Book 2006, 266-269.