Pediatric News

Tuesday, April 29, 2008

Issue 4, April 2008

Welcome to the April 2008 issue of the Pediatric Unit Newsletter. We have selected several interesting cases along with a review of Refractory Kawasaki’s Disease.

We would like to thank Dr. Inna Gofman for all her hard work, enthusiasm and dedication to our newsletter for the past two years. Her detailed case selections were much appreciated. We would therefore like to take this opportunity to welcome Dr. Jennifer Cohen as a new editor. Dr. Cohen has been an integral part of the hospitalist division for over six years. Her expertise and health care experiences in Africa bring a thoughtful perspective to our group.

Please feel free to contact us with any comments or suggestions.

Your Editors,

Jennifer Do, M.D. (DoJH@sutterhealth.org)
Jennifer Cohen, M.D. (cohenj @sutterhealth.org)

Who Have We Been Admitting?

There has been a decrease in the rate of RSV admissions in these past weeks. However, respiratory illnesses, including pneumonia, bronchiolitis and asthma still constituted the majority of hospitalizations. ALTE, fever without a source in a neonate, and gastroenteritis with dehydration remain common. Two adolescent patients required IV fluid rehydration and parenteral pain medication associated with their mononucleosis. Conspicuously minimal were admissions for influenza related illness.

Interesting Cases of the Month

A former 26 week neonate, recently discharged from the NICU presented to his primary physician for a regular follow- up visit and was found to have a fever of 102.3 and tachypnea. His review of systems was negative other than for poor feeding and fever. Sepsis workup yielded E Coli from a catheterized urine specimen and from the CSF. The blood culture was notably sterile. His hospital stay was complicated by apnea and seizures. He received 3 weeks of IV ampicillin and was discharged home at his baseline with close follow up with his pediatrician.
A 10 year old previously healthy male presented with a 2 day history of diffuse skin rash, mouth sores, and low-grade fever. The patient first noted an itchy rash on his face and neck, along with headache, while taking bactrim for a right knee cellulitis. Over the next 24 hrs, the headache and itching improved but the rash spread further down his trunk. The patient was taken to the ED where he was treated with prednisone, epinephrine, and benadryl prior to being discharged home. The next morning, he awoke with swollen lips, several painful mouth sores that made it difficult for him to swallow, and “stinging” eyes. The patient returned to the ED where he was found to have a low-grade fever, received one dose of solumedrol, and was admitted to the CPMC Pediatric Ward for supportive management of presumed Stevens-Johnson syndrome.
After admission, the patient developed significant conjunctivitis and mucositis in his oral cavity, with desquamation and worsening mouth pain. Ophthalmolgy was consulted and recommended moxifloxacin ophthalmic drops for his severe conjunctivitis. He also developed perianal erythema for which he was started on a topical balm. He received parenteral nutrition due to his mucositis and prolonged inability to adequately tolerate oral intake. For pain management, he was treated with morphine PCA, magic mouthwash, and chloraseptic spray. His skin rash resolved relatively quickly, but his mucositis continued to evolve over his hospitalization to include esophagitis with associated chest pain. He was started on Protonix and Benadryl, with some relief. He was discharged home on hospital day 8 once his pain and oral intake significantly improved with close follow up with his pediatrician.
A 7-week old girl born at term after an uncomplicated pregnancy was referred for evaluation of marked jaundice since birth. The parents reported that she has had yellow eyes since birth. The yellow color had increased in intensity and begun to involve the patient’s skin as well. She was feeding well with breastmilk and formula. The parents denied a history of dark urine, clay-colored stools, vomiting, diarrhea, or irritability. Upon admission, physical exam was notable for normal vital signs, icteric sclerae, normal cardiorespiratory exam, no hepatosplenomegaly, and marked, diffuse jaundice of the head, chest, abdomen, and extremities. Initial labs indicated a direct hyperbilirubinemia of 10.3 (total 11.9). With GI consulting, we initiated an evaluation for direct hyperbilirubinemia, with the differential diagnosis including biliary atresia, sepsis, hypothyroidism, panhypopituitarism, inborn errors of metabolism, and genetic syndromes (such as Alagille syndrome). Labs and cultures were sent to evaluate for sepsis, hypothyroidism, and panhypopituitarism, all of which were normal. Admission labs evaluating for metabolic causes of cholestasis included: hepatitis panel, plasma amino acids, alpha-1 antitrypsin, urine organic acids, urine CMV, and urine reducing substrates. Ammonia and hepatic transaminases were elevated. Alpha-1 antitrypsin level was normal. Cholesterol was markedly elevated. A HIDA scan was done to evaluate for biliary atresia, and it was notable for lack of biliary excretion. An ultrasound showed contracted gallbladder, and the liver biopsy was inconclusive but showed signs of inflammation. A chest x-ray obtained to screen for the "butterfly vertebrae" characteristic of Alagille's syndrome was negative. The patient was transferred to UCSF where the intraoperative cholangiogram was negative for biliary artesia. At this time, there is no definitive diagnosis for this patient.
A 3 month old former 34 week baby presented with an 8 day history of intermittent abnormal movements that were increasing in frequency daily. The parents noted left hand twitching, lip smacking, and eye blinking, and they felt that the baby was aware during all of these episodes. He had not had any fevers, coughing, runny nose, vomiting or diarrhea. He had been eating well until the day of admission when his decreased oral intake prompted the parents to take the baby to the ED. He was then transferred to the ward for further evaluation. He initially was started on ceftriaxone and acyclovir after a lumbar puncture was performed for concerns of an infectious etiology for his seizures. A head CT scan was normal. A neurology consult was obtained and the EEG showed focal, sharp waves in the right parietal region. The head MRI revealed cortical dysplasia. A diagnosis of infantile spasms was made and the infant was started on Keppra and ACTH. The seizure frequency decreased and he was discharged home with close follow up with his pediatrician and the neurologist.
A one year old boy presented with a two day history of fever, irritability and vomiting. The parents also noticed that moving his extremities made him uncomfortable, and that he refused to lie on his abdomen or crawl. He was seen at an outside ED, where he had labs drawn, received ceftriaxone, and had an abdominal CT which was negative. He subsequently developed an allergic reaction to the contrast dye, with respiratory difficulty and urticaria. He remained in the outside hospital overnight for observation after this reaction. The next morning, his PMD visited him and noted conjunctival injection, swollen hands and feet, and chapped lips. He was transferred to CPMC for evaluation and management of Kawasaki disease. Initial labs showed WBC 11.3K with 84% PMNs, albumin 3.4, ESR 37, CRP 11.4 (0-8), AST 171, ALT 137. The CBC, UA, and blood culture were all benign. Because of his extreme irritability, he had an LP, head CT, and EEG, the results of which were all normal. He was given high dose ASA (75 mg/kg/d) and IVIG (2g/kg) on day 3 of illness, which led to a febrile response and an apparent seizure that was treated with IV Ativan. The first echo noted prominent coronary arteries without definite abnormality. Fever, conjunctivitis, mucositis, and rash had worsened on day 5 of illness, so he was slowly infused with a second dose of IVIG (2g/kg), which he tolerated. His second echo showed no interval change. Repeat labs noted CRP 16.4, ESR 47, albumin 2.1, and normal LFTs. He was subsequently given an albumin infusion. On the 6th day of illness, he received high dose IV methylprednisolone (30 mg/kg) for persistent fever and marked irritability. Subsequently, he became afebrile with improvement in conjunctival injection and rash. Repeat ESR was 62 and the 3rd echo on illness day 7 showed no interval change. Aspirin was decreased to low dose and he was discharged home. He still had moderate irritability and persistently red lips and pedal edema but was alert and afebrile.

The day after discharge, he developed a fever of 102 F with increased irritability, body stiffness, and emesis. There was also relapse of conjunctival injection and papular skin rash. He was readmitted to CPMC and was afebrile. He promptly received a 3rd infusion of IVIG (day 9 of illness) and continued on low dose aspirin with clinical improvement over the next 24 hours. The rash, conjunctivitis, and mucositis resolved and patient remained afebrile. He was discharged home on methylprednisolone (2 mg/kg) with a tapering dose schedule for a total of 6 days.

After discharge, he improved clinically for 5 days until he again spiked a fever to 100.6 and had reemergence of his conjunctivitis. Two days later, he also became more irritable and weak, but was more aware and alert of his surroundings than during initial hospitalization. His lips remained red, cracked, and bleeding, and he was refusing most oral intake. He had finished the 6 day steroid taper and was still taking his low dose aspirin.

He was readmitted 8 days after his second discharge. His labs just prior to this admission were notable for CRP 13.2, and platelet count 1,484,000. Repeat echo on the third admission noted the presence of two small aneurysms in the proximal right coronary artery. He did not receive IVIG or any additional treatments during the third hospital stay. He remained afebrile overnight but continued to be intermittently irritable and refused to crawl or bear weight on his extremities. Although the high platelet count and coronary artery aneurysms support a diagnosis of Kawasaki disease, the refractory nature of his illness warranted evaluation for other explanations of his illness, so he was transferred to UCSF for rheumatology evaluation.

Review of the Month: Refractory Kawasaki's Disease

Kawasaki’s Disease (KD) is a common childhood vasculitis and presents with prolonged fever, mucocutaneous changes, and systemic inflammation. The cardiac sequelae are the most significant cause of morbidity and mortality in this disease. These complications include coronary artery aneurysms, myocardial infarction, heart failure, arrhythmias, peripheral arterial ischemia. Timely diagnosis and IVIG therapy can decrease the development of coronary artery aneurysms.

However, 10 to 15 percent of patients with KD will remain febrile more than 36 hours after their initial treatment with IVIG. There are some patients who will respond to additional doses of IVIG whereas others continue to manifest ongoing vasculitis despite multiple doses. These patients appear to be resistant to IVIG therapy and are at significant risk for developing coronary artery aneurysms. A chronic vasculitis, such as polyarteritis nodosa or juvenile rheumatoid arthritis , should be considered in the differential diagnosis if the illness persists beyond one month.

Potential risk factors for refractory KD noted in retrospective studies include initial IVIG treatment at or before the fifth day of illness, male sex, and recurrent KD. Other retrospective studies have also observed that age less than 1 year, initial IVIG treatment before the fourth day of illness, hyponatremia, elevated transaminases, elevated C-reactive protein, and platelet count under 300,000/mm2 increased the likelihood for additional therapy. These patients may have more advanced disease at presentation, greater risk for coronary artery aneurysms, and therefore warrant more aggressive therapy.

Patients with persistent or recurrent fever 36 hours after completion of their initial dose of IVIG are often treated with a second dose of IVIG. Retreatment with IVIG 2 gm/kg for a total cumulative IVIG dose of 4 gm/kg is recommended. The majority of patients will have resolution of their fever after a second, and sometimes third dose of IVIG. It is not understood why some children require repeated infusions of IVIG. One hypothesis proposes the persistence of circulating inflammatory mediators in nonresponders.

Refractory cases of KD require alternative therapies because of the increased risk of cardiac complications. Glucocorticoids, such as pulsed-dose methylprednisolone 30mg/kg/day for one to three days, have been safely utilized. Methylprednisolone is recommended for children who have active vasculitis despite two infusions of IVIG. Children with persistent fever and ongoing vasculitis despite this regimen should receive an anti-TNF-alpha agent, plasmapheresis, cyclosporine, or cyclophosphamide.

Anti-TNF-alpha agents such as infliximab, etanercept, and pentoxifylline have been used. A single IV dose of infliximab 5mg/kg could be given after two doses of IVIG and after one to three doses of methylprednisolone. These are potent immunosuppressive agents with a longer half-life than glucocorticoids. A thorough search for an infectious etiology for the persistent fever should be excluded prior to their use.

Plasmapheresis, cyclosporine, and cyclophosphamide have also been reported in refractory Kawaski’s disease. The limited data, unclear efficacy, risks and side effects of these alternative modalities require the supervision and guidance of a physician with expertise in treating children with refractory KD.

Pediatric Grand Rounds Schedule
Grand Rounds are held at Bothin Auditorium at the California Campus (3700 California Street) in San Francisco on Fridays at 9 a.m. unless indicated otherwise.

May 2
The Role of the Pediatrician in the Management of Eating Disorders
Neville Golden, M.D.
Chief, Division of Adolescent Medicine
Lucile Packard Children’s Hospital