December 2001

A 14-year-old girl was transferred from another hospital for further evaluation and treatment of a febrile illness with a rash, a sore throat, myalgias, emesis and headaches. The onset of her illness was about a week earlier with the abrupt onset of throat pain, anorexia, one episode of emesis and fever in the 103º-104º F range, followed within hours by a rash that first appeared on her legs. Her myalgias were migratory, with arthralgias soon developing, involving small joints, such as her wrists. Her evaluation at the referring hospital included a complete blood count (CBC), urinalysis, Chem-7, liver enzymes, antistreptolysin-O titer, strep screen, antinuclear antibody, rheumatoid factor, head CT scan, chest radiograph and cerebrospinal fluid analysis with opening pressure; all being normal. She was treated empirically with ceftriaxone (Rocephin, Roche) and clindamycin (Cleocin, Pharmacia) without improvement.

Her past medical history, travel history, animal and insect exposure were all negative or unremarkable. Her immunizations were up-to-date, and there were no known sick contacts. However, her family history is positive for her father having ankylosing spondylitis.

Examination revealed a febrile 14-year-old female who appeared somewhat ill and uncomfortable with a maculopapular rash as shown in figures 1-6. There was no conjunctivitis or any other mucous membrane inflammation seen. Neither desquamation nor nail changes were found. Additionally, she complained of pain on palpation of various muscles about the neck, face and back. She also complained of pain on range-of-motion testing of multiple joints, mostly about the hands, wrists, neck, ankles and feet, but no swelling was appreciated. The rest of her exam was normal.

Upon arrival, doxycycline was started empirically for possible rickettsial disease pending serologic testing (which turned out negative). A repeat CBC on admission revealed moderate leukocytosis with normal platelets and an erythrocyte sedimentation rate of 110. Realizing that you cannot make a definite diagnosis with only the above information, of the following, make the best choice.

What’s Your Diagnosis?

1. Atypical Kawasaki disease
2. Rheumatic fever
3. Juvenile rheumatoid arthritis
4. Systemic lupus erythematosus

Answer

This child turned out to have JRA, juvenile rheumatoid arthritis (C). Infectious disease consultants are often asked to evaluate these patients during the initial assessment because of the fever and difficulty in securing the diagnosis because of the broad differential with this cluster of signs and symptoms. This is especially true when you are still in the acute phase of the illness. Also, the patient almost invariably receives empiric antimicrobials during the acute stage.

STAR complex

By definition, the diagnosis of JRA cannot be made until typical manifestations of the disease are present without any other explanation for at least 3 months. In fact, our rheumatologists referred to her diagnosis initially as STAR complex, which is an abbreviation for Sore throat, Temperature elevation, Arthritis and Rash. I have some vague memory of seeing this descriptive term somewhere in the past, but could not find it anywhere in the indices of current pediatric, infectious disease, rheumatology nor immunology textbooks. Neither could I find any reference to STAR complex in any of the similar current journals over the last several years. Nonetheless, this designation makes about as much sense as anything else pending fulfilling the clinical and laboratory criteria for a definite diagnosis. If anyone knows of a reference to STAR complex, please e-mail me and we will add it to the January issue.

This patient was hospitalized for 11 days plus a few spent at the referring hospital. For the few cases of JRA that I have been involved with, this duration of hospitalization is about average for working through the various other diagnostic possibilities. She was initially treated with aspirin, then prednisone, but ultimately required methotrexate to control the inflammation. Follow-up over 3 years, however, reveals that she had to change to hydroxychloroquine sulfate (Plaquenil) due to side effects of the methotrexate.

Systemic lupus erythematosus

While this patient’s facial rash resembles the butterfly rash of systemic lupus erythematosus (SLE), her ANA and other laboratory and clinical findings did not fit enough criteria for this diagnosis. The ANA is almost always positive in SLE, especially during exacerbations. Additional supportive lab data for SLE include hemolytic anemia, leukopenia and evidence of renal disease. Additional clinical findings include serositis with pleuritic pain and/or evidence of pericarditis, oral ulcers and other cutaneous findings. For these diagnostic criteria and discussion of the other rheumatic diseases of childhood, I would refer you to the current, 16th edition, of Nelson’s Textbook of Pediatrics. There is a most excellent review of these conditions, primarily edited by Michael L. Miller, MD, from Chicago. Several prior editions were edited by Jane Green Schaller, MD, chair, department of pediatrics at Tufts University and New England Medical Center, Boston. Dr. Schaller had been refining this section of Nelson’s for about three decades. My first copy of Nelson’s is the tenth edition, 1975, when I was a student. At that time, Dr. Schaller was with the Department of Pediatrics at the University of Washington School of Medicine, Seattle, and from what I could gather, co-authored this section with her department chair, Ralph Wedgwood, MD. Because of my short-term memory problem and thickheadedness, I still frequently refer to this section of Nelson’s textbook to get clarification of these confusing and mysterious diseases. Dr. Schaller’s style, and now Dr. Miller’s, makes it easy for even me to understand. Perhaps it should be titled “Rheumatic Diseases for Dummies.”

Atypical Kawasaki disease

Atypical Kawasaki disease (AKD) is certainly in the differential of a febrile child with a rash. However, things that mitigate against AKD are the child’s age, and a lack of any of the other 4 criteria (in addition to rash); conjunctival inflammation, other mucous membrane inflammation (including mouth, urethra, anal or vaginal mucosa), adenopathy, or extremity changes with swelling of hands or feet. Kawasaki disease would be almost unheard of, typical or atypical, in a 14-year-old. In fact, it is very uncommon in children even older than 8. The vast majority is less than 5-years-old, with over 50% being less than 2. Typical KD requires fever for at least 5 days with at least 4 of the 5 criteria noted above, and no other explanation. In our experience here at Scott & White, typical KD has become very uncommon. However, we are diagnosing more atypical cases all the time. These are cases where only 3 criteria are present with fever and no other explanation, or even fewer criteria if there is any evidence of myocardial disease or coronary artery aneurysm. Like those with typical KD, children with atypical KD will also usually have marked thrombocytosis and desquamation in the subacute stage (week 2-3). All these patients are treated as typical KD cases with IVIG and aspirin as recommended in the 2000 Red Book. By the way, the Visual Red Book has some excellent pictures of typical KD. Figures 7-16 are from 2 patients with atypical KD. The conjunctivitis is hard to photograph, but I think you can see the discrete erythema. This has to be evaluated in a child who is not crying for obvious reasons. The extremity findings can also be subtle. I usually ask the parents if the child’s hands and feet look the same to them as usual without loading the question. If they answer no, then I count the extremity changes even if I don’t notice anything unusual. Many babies’ hands and feet look pink and puffy. The parents are the best source for differentiating this. The patient in figures 17-20 presented with fever and the rash seen with only extremity puffiness according to the mother. No other criteria were seen. However, during the second week of illness, he still had fever and an elevated ESR with marginal thrombocytosis and an echocardiogram that revealed a subtle enlargement of one of the arteries. He was given IVIG and aspirin with immediate resolution of his fever, but on further follow-up it appeared that he actually had JRA. Note also that his rash was almost absent in the inguinal area where it is usually more intense in known KD.

Rheumatic fever

Rheumatic fever is seen rarely nowadays. But it always has the potential to make a comeback. Of course, it is the major nonsuppurative complication of a group A streptococcal (GAS) infection, usually of the throat. The exact pathogenesis remains uncertain, but appears to be immune-mediated. T.D. Jones proposed certain diagnostic criteria in 1942 based on a study of 1,000 patients (RF was much more common in those prepenicillin days). The Jones Criteria have been modified over the years, but still rely on various combinations of major and minor findings, all of which depend on evidence of a recent GAS infection by culture, antigen testing, or serology. The patient presented above had no laboratory evidence of recent GAS disease.

Excellent reviews of rheumatic fever can be found in almost any pediatric text, but for a really detailed description of the clinical manifestations, go to an old text. For example, the 6th edition (1954) of Nelson’s textbook dedicates 13 pages to rheumatic fever, whereas the 16th edition (2000) uses about 4½ pages (although larger in size). Holt’s Diseases of Infancy and Childhood, 10th edition (1936) gives 18 pages to rheumatic fever. It just does not pay to print in great depth, information on a condition that has become so uncommon, but beware and keep it in mind. Like other disastrous GAS conditions (ie, necrotizing faciitis), it has a way of surfacing in geographic clusters.

I would like to wish you all a happy holiday season and a healthy and prosperous new year. I’m sure we all share the same desire to see peace come to our country and to the rest of the world as soon as possible.