INTRODUCTION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

The etiologies of respiratory distress in the term neonate include infection, congenital anomalies (heart or lung), pulmonary hemorrhage or edema, aspiration, pneumothorax, or transient tachypnea. Rarely, interstitial lung disease can cause tachypnea and hypoxemia in infants within the first month of life, and it is usually attributed to a postnatal infectious etiology (1). We describe a 2-wk-old infant with biopsy-proven eosinophilic pneumonia whose management was complicated by the development of steroid resistance. We describe a case of idiopathic eosinophilic pneumonia in a neonate, discuss conventional management strategies, and report a beneficial response to oral cyclosporin.

	CASE REPORT

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

A 2-wk-old boy presented to the emergency department of Kosair Children's Hospital (Louisville, KY) with tachypnea, perioral cyanosis, and retractions. He had been delivered at an outlying hospital at gestation week 42 by emergency cesarian section for fetal bradycardia, with unstained amniotic fluid. The pregnancy had been complicated by maternal smoking and asthma (untreated) as well as a urinary tract infection treated with nitrofurantoin during the second trimester. Tachypnea (80-100 breaths/min) in the immediate newborn period had prompted an evaluation that demonstrated sterile cultures of blood, urine, cerebrospinal fluid, as well as a normal echocardiogram and electrocardiogram. The baby was discharged at 8 d of age without therapy.

At presentation, the infant had subcostal and suprasternal retractions with a respiratory rate (RR) of 80-100 breaths/min on room air. Auscultation revealed symmetrically clear breath sounds. Although a pulse oximeter demonstrated a saturation of 80-83% on room air, no cyanosis was evident. He was afebrile, with a pulse of 120/min and a blood pressure of 97/51 mm Hg. His weight was 4.2 kg (75%) and his length was 56 cm (90%). He had physiologically split, normal heart sounds, without murmur. The remainder of the examination was normal.

A chest roentgenogram revealed bilateral, diffuse pulmonary interstitial infiltrates (Figure 1). The white blood cell count was 14,100/mm³ with 39% neutrophils, 40% lymphocytes, 11% monocytes, and 7% eosinophils (absolute eosinophil count, 987 cells/mm³). The hemoglobin concentration was 18.9 g/dl, and the platelet count was 482,000/mm³. Blood, urine, and cerebrospinal fluid (CSF) cultures were sterile.

View larger version (122K): [in this window] [in a new window]   Figure 1.   Chest roentgenogram at initial presentation, showing diffuse bilateral interstitial infiltrates.

The patient was initially treated with ampicillin, gentamicin, erythromycin, oxygen, and nebulized albuterol and cromolyn. An infant pulmonary function test (PFT) demonstrated mild restrictive lung disease; total pulmonary compliance was 0.75 ml/cm H₂O/kg (normal for age,  1.0 ml/cm H₂O/kg). Passive pulmonary mechanics, including airway resistance and total pulmonary compliance, were measured using the single occlusion passive flow-volume technique as previously described (2). A computerized tomography (CT) scan of the lungs demonstrated diffuse interstitial and alveolar opacities (Figure 2). A repeat echocardiogram demonstrated normal cardiac anatomy with normal pulmonary veins. There was no evidence of pulmonary hypertension. An open lung biopsy was performed, which revealed a prominent infiltrate of eosinophils in the lobular interstitium and within small arteries (Figure 3). Special staining of the biopsy revealed no mast cells. No evidence of acid-fast organisms, Pneumocystis carinii, or viral inclusions was present on histology. Viral, bacterial, and fungal tracheal aspirate cultures were negative. Chlamydia-specific polymerase chain reaction (PCR) and culture, as well as Mycoplasma-specific PCR on throat swab, were negative. The PCR is a sensitive test for detecting Chlamydia and Mycoplasma on throat swab (6, 7). Cultures, PCR, and serology for Pertussis were negative. No exposure to dog or cat feces (parasites) was reported. The patient responded (RR, 50-60/min) to methylprednisolone (2 mg/kg every 6 h for 4 d). Although no reversibility with bronchodilators could be demonstrated on the infant PFT, he responded clinically with decreased retractions after administration of nebulized albuterol. He was subsequently discharged with supplemental oxygen (1 L/min), prednisone (2 mg/kg/d), and nebulized albuterol and cromolyn.

View larger version (149K): [in this window] [in a new window]   Figure 2.   Computerized tomography (CT) scan of the chest, showing diffuse alveolar and interstitial opacities.

View larger version (143K): [in this window] [in a new window]   Figure 3.   Lung biopsy showing a prominent infiltrate of eosinophils in the lobular interstitium and in surrounding and transversing small arteries, with alveolar septal widening present as well. (H&E; original magnification, ×250.)

The patient was hospitalized 2 wk later for a deterioration in respiratory status, with increased retractions and tachypnea (RR, 100 breaths/min). An immunologic evaluation was undertaken. CH₅₀ (50% hemolytic complement), anti-neutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), and anti-nuclear antibody (ANA) assays, as well as a Raji cell assay (for detection of circulating immune complexes) were normal or negative. The erythrocyte sedimentation rate was 3 mm/h. Immunoglobulin concentrations were normal for his age. The infant responded (RR, 48 breaths/min) to intravenous methylprednisolone (2 mg/ kg every 6 h for 3 d), but his respiratory status deteriorated (RR, 70-80 breaths/min) when this was tapered to oral prednisone at 2 mg/kg/d. Intravenous gamma globulin (IVIG; 500 mg/kg daily for 2 d) was given empirically, and resulted in a dramatic improvement (RR, 30-40 breaths/min) in respiratory status. Two days after the initial beneficial response to IVIG, the patient's RR increased to 60 breaths/min with intermittent retractions. He was discharged on prednisone (2 mg/kg/d), oxygen (0.5 L/min), and nebulized albuterol and cromolyn.

At 8 wk of age he was again hospitalized owing to an exacerbation of respiratory symptoms (RR, 80-100 breaths/min). Despite 6 wk of corticosteroid therapy with a minimum daily prednisone dose of 2 mg/kg, total lung compliance had decreased to 0.59 ml/cm H₂O/kg. Oral cyclosporin A (Neoral; 5 mg/kg once daily) was empirically initiated. This resulted in a dramatic clinical response (RR, 40 breaths/min) over the first week, with a marked decrease in the work of breathing and oxygen requirement. After 3 wk of cyclosporin, the prednisone dose was tapered to 1.5 mg/kg given every other day. A repeat CT of the chest demonstrated resolving alveolar infiltrates with residual markings at the lung bases (Figure 4). Total pulmonary compliance improved to 0.94 ml/cm H₂O/kg. The patient, monitored for an additional 4 mo, had an RR of 30-40 breaths/min and no retractions, and is receiving a tapering dosage of the oral prednisone.

View larger version (150K): [in this window] [in a new window]   Figure 4.   Computerized tomography scan of the chest, showing resolving alveolar infiltrates with residual markings at the base.

	DISCUSSION

TOP ABSTRACT INTRODUCTION CASE REPORT DISCUSSION REFERENCES

Eosinophilic pneumonia is characterized by pulmonary eosinophilic infiltrates, with or without peripheral eosinophilia (8). In adults this may manifest as a chronic (8, 9) or an acute (10, 11) illness. It is uncommon in children, with only a handful of cases documented (12). A case of pulmonary eosinophilic arteritis has been described in a full-term fetus (15). Pulmonary eosinophilia in infancy has also been associated with sudden infant death syndrome (SIDS) (16).

Although pertussoid eosinophilic pneumonia has been reported in infants within the first month of life (12), several lines of evidence suggest that this patient's illness was not related to a postnatal infection. All cultures, PCR, and lung biopsy stains were negative for infectious pathogens. The immunoglobulin profile, before immunoglobulin infusion, was normal for his age, an unusual finding in symptomatic infants with respiratory infections. In addition, coughing was never present during this illness.

The etiology of the eosinophilic pneumonia in this infant is unknown. Serologic studies to screen for connective tissue diseases were negative. Nitrofurantoin has been implicated as causing eosinophilic pneumonia in adults (8, 17) and has been shown to induce both cellular and humoral immune responses (18). The vascular infiltration of eosinophils as revealed by lung biopsy suggests a hypersensitivity vasculitis. However, it is unlikely that maternal use of nitrofurantoin during pregnancy initiated an acute hypersensitivity phenomenon (10) in this infant, because nitrofurantoin does not cross the placenta and all reported cases of drug-induced eosinophilic pneumonia have responded well to corticosteroids (8- 11). Both animal and human studies have indicated no teratogenic effects from nitrofurantoin use during pregnancy (19).

Glucocorticoids are the cornerstone of contemporary management of eosinophilic pneumonia (8, 13, 14). This class of drugs interferes with the transcription of a number of proinflammatory genes whose products are necessary for eosinophil maturation, proliferation, chemoattraction, adhesion and migration, activation, and longevity. These include the genes for interleukin 3, interleukin 4, interleukin 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and a variety of chemokines (20). Our patient initially improved with therapy, but 2 wk later his respiratory status deteriorated while receiving prednisone at 2 mg/kg/d. This suggests glucocorticoid resistance (23), although a repeat lung biopsy to demonstrate persistent interstitial eosinophilia was not pursued. Steroid resistance is a poorly understood phenomenon previously reported in patients with asthma, and may result in part from downregulation of glucocorticoid receptors as well as ineffective interactions between the receptor and the transcription factor, activator protein 1 (24, 25).

The tissue mast cell may contribute to interstitial eosinophilia through local production of interleukin 1, interleukin 4, interleukin 5, and tumor necrosis factor  (22, 26). Cromolyn sodium has dual beneficial roles. This drug prevents mast cell activation and reduces eosinophil cytotoxic activity (22, 27).

Intravenous gamma globulin provided a temporary beneficial response. This medicine is nonspecific; it is effective in a variety of noninfectious immunologic disorders (Kawasaki disease, idiopathic thrombocytopenia purpura, asthma), as well as infectious conditions (human immunodeficiency virus [HIV], posttransplantation viral illnesses, enteroviral disease). Although the benefit in our patient was temporary, gamma globulin should be considered in steroid-refractory eosinophilic pneumonia, after a thorough serologic evaluation has been performed.

Cyclosporin therapy was initiated owing to its reported benefit in asthma, and the initial response to other immunomodulatory therapies. We speculate that this infant's illness was probably mediated by cytokines. Cyclosporin inhibits the transcription of numerous lymphokines produced by T cells, including interleukin 4, interleukin 5, and GM-CSF (22, 28, 29). Interleukin 4 upregulates endothelial expression of vascular cell adhesion molecule 1 (VCAM-1), which is important for migration of eosinophils from the circulation (30). Interleukin 5 and GM-CSF serve to promote eosinophil development and maturation from bone marrow granulocytic cell lines (31, 32), as well as to prolong their survival in peripheral tissues by inhibiting apoptosis (33). The beneficial response to cyclosporin may also have resulted from inhibition of T cell stimulation of antigen-presenting cells (28). Activated antigen-presenting cells are capable of stimulating tissue epithelial cells to release eosinophil chemoattractants (22).

This case report describes idiopathic eosinophilic pneumonia in a neonate. It is unusual in that symptoms began in the immediate postnatal period. Although corticosteroids and cromolyn sodium should be used as initial therapy, our experience suggests that strong consideration should be given to the use of cyclosporin and intravenous gamma globulin in children experiencing glucocorticoid resistance or excessive side effects.