Acute respiratory distress syndrome in a child with Kawasaki disease.
Key Words: Kawasaki disease, acute respiratory distress syndrome, intravenous immunoglobulin, systemic inflammatory immune response
Kawasaki disease (KD) is a systemic vasculitis characterized by fever for 5 days or more, along with four of five associated symptoms (polymorphous skin rash, nonexudative conjunctivitis, mucosal erythema, cervical lymphadenopathy greater than 1.5 cm, and palmar/plantar edema and/or erythema). (1) Pulmonary complications with KD have been reported infrequently. Severe pulmonary disease has been reported in a patient with KD treated with intravenous immunoglobulin (IVIG) after 10 days of fever. (2) We present a case of severe pulmonary disease in a patient with KD progressing to acute respiratory distress syndrome (ARDS) after the patient was treated with IVIG within the first 10 days of fever.
A 5-year-old male was transferred to the University of Mississippi Medical Center with prolonged fever, abdominal pain, and respiratory distress. On the fifth day of fever, he presented to his local hospital with nausea, vomiting, a polymorphous erythematous rash, nonexudative conjunctivitis, red lips, and a strawberry tongue. He was initially treated with intravenous fluids and doxycycline. The next day he developed erythema of his hands and feet and frequent liquid stools. A diagnosis of KD was made, and the patient was given IVIG and high-dose (80 mg/kg per day) aspirin. Before a full 2 g/kg dose of IVIG could be completed, generalized edema, abdominal distension, and respiratory distress developed. A chest roentgenogram (CXR) revealed bibasilar infiltrates.
The patient was transferred to the University of Mississippi Medical Center on the seventh day of fever. At admission, his temperature was 100.1[degrees]F, pulse rate was 131 beats/min, respiratory rate was 48 breaths/min, and blood pressure was 75/37 mm Hg. Confluent erythroderma over the entire body was noted. The abdomen was distended and very tender to palpation. The patient was treated with intravenous fluids, a dobutamine infusion, clindamycin, doxycycline, and ceftriaxone. An echocardiogram showed a small pericardial effusion, normal ejection and shortening fractions (60% and 30%, respectively), and no coronary changes. Laboratory studies showed a normal white blood cell count (8,400/[mm.sup.3]) with 38% band forms, mild anemia (hemoglobin, 9.4 mg/dL), thrombocytopenia (93,000/[mm.sup.3]), mildly abnormal coagulation studies [Prothrombin and activated partial thromboplastin times were 13.6 (normal range, 11 to 14 seconds) and 40.5 (normal range, 23 to 36 seconds) seconds, respectively]. Fibrin split products were greater than 10 but less than 40 mg/mL, hypoalbuminemia (1.7 g/dL) and a C-reactive protein of 16.1 mg/dL. An arterial blood gas on 2 L/min of oxygen showed a pH of 7.40 with partial pressures of oxygen (Pa[O.sub.2]) and carbon dioxide of 66 and 37, respectively.
The patient was admitted to the pediatric intensive care unit. On the second day of hospitalization, his breathing became less labored. He remained febrile but was hemodynamically stable. He was given 2 g/kg of IVIG over a period of 12 hours. The next hospital day, his abdominal pain improved slightly, but his oxygen requirement continued to increase. Within 36 hours, he had respiratory failure requiring intubation and mechanical ventilation. A CXR showed a normal-sized heart with bilateral alveolar filling (Figure). The patient required significant respiratory support to maintain adequate oxygenation with maximum ventilator settings consisting of a positive end-expiratory pressure of 12 mm Hg and fraction of inspired oxygen (FI[O.sub.2]) of 60%. The ratio of Pa[O.sub.2] to FI[O.sub.2] remained approximately 100. Central venous pressure readings were between 7 and 12 mm Hg. Echocardiography continued to show normal left ventricular function. The patient remained febrile. No pathogens were isolated from blood, urine, or tracheal aspirate cultures.
On the ninth day of hospitalization, day 15 of fever, an echocardiogram revealed normal left ventricular function with a prominent and irregular left coronary artery. The child was given another 2 g/kg dose of IVIG over a period of 24 hours. A heparin infusion was begun. The patient became afebrile within 2 days. He slowly recovered and was extubated on the 18th day of hospitalization. Supplemental oxygen was discontinued before hospital discharge.
Three weeks into the patient's illness, an echocardiogram showed several aneurysms in the right and left coronaries measuring 3.5 to 5 mm in size. During this time, desquamation of the patient's hands and feet occurred. The child was discharged one month after admission on oral warfarin and low-dose aspirin. Warfarin was discontinued 1 month after discharge, since no large (6 mm or greater) aneurysms were seen by echocardiography. One year after discharge, echocardiography showed marked left coronary enlargement with a distal 6 mm aneurysm. Cardiac catheterization was then performed, revealing a 4.5-mm aneurysm in the left anterior descending artery, a dilated proximal circumflex artery, a normal right coronary artery, and no stenosis.
Clinical, pathologic, and radiographic evidence of pulmonary disease has been reported in KD cases. Umezawa et al (3) retrospectively found approximately 15% of KD cases to have abnormalities on CXRs such as presence of a reticulogranular pattern, peribronchial cuffing, atelectasis, air trapping, and pleural effusions. In this series, abnormal CXRs were associated with longer duration of fever, higher C-reactive protein levels, and an increased incidence of coronary lesions, pericardial effusions, and paralytic ileus and nervous system abnormalities. Pneumonia has been the prominent symptom in both classic and atypical cases of KD leading to a delay in diagnosis. (2,4,5) Most of the reported pulmonary disease in KD has been mild. However, in the report by Voynow et al, (2) interstitial lung disease with pleural effusions were seen in a child with KD who became hypoxic. Unlike our case, none of the other reports of pulmonary disease in KD have clearly described progression to ARDS.
ARDS is strictly defined as a condition involving impaired oxygenation with the Pa[O.sub.2]/FI[O.sub.2] ratio of 200 or less; bilateral pulmonary infiltrates on CXR; and a pulmonary artery occlusion pressure of 18 mm Hg or less or no clinical evidence of elevated left atrial pressure. (6) Our patient did not have his pulmonary artery occlusion pressure directly monitored. However, no indirect evidence of elevated left atrial pressure was noted: his left ventricular ejection and shortening fractions remained normal as well as his central venous pressure readings. The cause of our patient's ARDS is unknown but probably resulted from a generalized capillary leak after a systemic inflammatory immune response.
Many studies have demonstrated that pulmonary findings in KD are due to an inflammatory process. Pulmonary arteritis was noted in a series of autopsied KD cases. (7) In a study by Rowley et al, (8) high numbers of IgA plasma cells were found in pulmonary vessels, the trachea, and peribronchial tissue. In a later study by Freeman et al, (9) immunohistochemical staining of inflammatory pulmonary nodules from two patients with KD revealed common leukocyte antigen and IgA positivity. Factor VIII staining was also high, suggesting presence of angiogenesis. These investigators proposed that the pulmonary nodules resulted from an IgA oligoclonal response to a respiratory antigen. (9)
Our patient met criteria for classic KD with four of five associated symptoms of KD and fever for 5 days or more without other explanation. The severity of his symptoms, particularly development of ARDS and his poor response to the first two doses of IVIG, led his physicians to suspect toxic shock syndrome (TSS). Clinical symptoms of TSS and KD are very similar, although fever may be more prolonged in KD. ARDS can occur in TSS and usually occurs as other symptoms of TSS are resolving. (10) It is not surprising that other investigators have reported cases of patients concurrently diagnosed with TSS and KD. (11-14) Microvascular leakage is part of the pathologic process in KD, TSS, and ARDS. (10,15,16) This increase in microvascular permeability may be due to vascular endothelial growth factor (VEGF). In a study by Terai et al, (16) patients with KD with higher post-IVIG treatment VEGF levels were more likely to be resistant to IVIG. Patients who were IVIG resistant were more likely to have weight gain after IVIG and have development of coronary aneurysms. IVIG has rarely been associated with transfusion-related acute lung injury. In the only published report of IVIG-associated transfusion-related acute lung injury, a patient had transient noncardiogenic pulmonary edema after receiving a large volume of IVIG over a period of 3 hours. The authors hypothesized that the rapid infusion of a large quantity of granulocyte antibody provided a stimulus for lung injury (17) It is recommended that the large volume of IVIG required for treatment of KD be given over 10 to 12 hours. (18) Our patient was given IVIG infusions over appropriate periods of time. Moreover, he showed signs of systemic vascular damage with the presence of ascites and peripheral edema, suggesting that his underlying vasculitis, not IVIG, was responsible for his acute lung injury. Although we cannot definitely rule out IVIG as a contributing factor to our patient's ARDS, his respiratory status improved simultaneously with resolution of his systemic signs of noncardiogenic edema and inflammation within days of receiving a third dose of IVIG. We postulate that in severe KD, significant vascular leakage occurs, placing the patient at risk for noncardiogenic edema, ARDS, and coronary disease.
1. Newburger JW, Takahashi M, Beiser AS, et al. A single intravenous infusion of gamma globulin as compared with four infusions in the treatment of acute Kawasaki syndrome. N Engl J Med 1991;324:1633-1639.
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8. Rowley AH, Shulman ST, Mask CA, et al. IgA plasma cell infiltration of proximal respiratory tract, pancreas, kidney, and coronary artery in acute Kawasaki disease. J Infect Dis 2000;182:1183-1191.
9. Freeman AF, Crawford SE, Finn LS, et al. Inflammatory pulmonary nodules in Kawasaki disease. Pediatr Pulmonol 2003;36:102-106.
10. Todd JK Toxic shock syndromes. In: Long SS, Pickering LK, Prober CG, cditors. Principles and Practice of Pediatric Infectious Diseases. New York: Churchill Livingstone; 1997.107-111.
11. Wiesenthal AM, Todd JK. Toxic shock syndrome in children aged 10 years or less. Pediatrics 1984;74:112-117.
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13. Davies HD, Kirk V, Jadavji, et al. Simultaneous presentation of Kawasaki disease and toxic shock syndrome in an adolescent male. Pediatr Infect Dis J 1996;15:1136-1138.
14. Skae CC, Stock AC, Ozuah PO, Correlates of toxic shock syndrome in Kawasaki disease. ABSTRACT Pediatr Res No. 1942.
15. Thickett DR, Armstrong L, Christie SJ, et al. Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164:1601-1605.
16. Terai M, Honda T, Yasukawa K, et al. Prognostic impact of vascular leakage in acute Kawasaki disease. Circulation 2003;108:325-330.
17. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268.
18. American Academy of Pediatrics. 2003 Red Book, Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, Illinois: American Academy of Pediatrics, 2003.
April Lynne Palmer, MD, Thomas Walker, MD, and J. Clinton Smith, MD
From the University of Mississippi Medical Center, Department of Pediatrics, Jackson, MS. Email: email@example.com
Reprint requests to April Lynne Palmer, MD, Department of Pediatrics, 2500 North State Street, University of Mississippi Medical Center, Jackson, MS 39216-4505.
Accepted April 20, 2005.
RELATED ARTICLE: Key Points
* Pulmonary disease may manifest in several different ways in Kawasaki disease (KD).
* Acute respiratory distress syndrome can occur in cases of severe KD.
* Patients with severe pulmonary findings in KD may be resistant to intravenous immunoglobulin.
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|Author:||Smith, J. Clinton|
|Publication:||Southern Medical Journal|
|Date:||Oct 1, 2005|
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