PEDIATRICS Vol. 106 No. 4 October 2000, pp. 835-837

EXPERIENCE AND REASON:
Respiratory Syncytial Virus Infection in Patients With Phagocyte Defects

	ABSTRACT

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Patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects.respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia.

We have encountered 3 cases of dense pulmonary consolidations attributable to respiratory syncytial virus (RSV) in patients with phagocyte immune deficiencies over the past 3 years. The patients' defects span neutrophil and monocyte problems, nonclassical settings for severe RSV infection.

As clinical immunologists or pediatricians, we manage patients with different primary immune deficiencies affecting the phagocytic system. Chronic granulomatous disease (CGD) is a phagocyte defect in which killing of catalase-positive bacteria and fungi is defective.¹ An impaired reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leads to recurrent life-threatening infections and tissue granuloma formation. Four genotypes of CGD have been described corresponding to mutations in the genes encoding gp91^phox, p47^phox, p67^phox, and p22^phox. Commonly encountered organisms in the setting of pneumonia, liver abscess, osteomyelitis, or skin infection are Staphylococcus aureus, Serratia marcescens, Burkholderia cepacia, Nocardia and Aspergillus sp. Patients frequently present with signs and symptoms of bacterial pneumonia. After prompt efforts to isolate the offending organism, (blood cultures, fine-needle aspirates, and/or bronchoscopy), the infection is treated empirically with appropriate antibiotics. In this setting, although uncommon, viral pneumonia caused by RSV may be mistaken for a bacterial or fungal infection.

A recently recognized defect of human phagocytes due to non- or dysfunctional interferon- receptors (IFNR) results from mutations in either the ligand-binding chain (IFNR1) or the signal-transducing chain (IFNR2).^2,3 Because IFN plays a major role in stimulating antimicrobial functions of monocytes and macrophages, patients with defective receptors acquire disseminated infections with mycobacterial species of low virulence.⁴ Certain viral infections in this patient group have been recently recognized to be unusually severe and protracted.^5,6 We encountered a patient with IFNR1 deficiency who developed severe pneumonia and respiratory failure attributable to RSV infection.

RSV, the offending pathogen for the patients in this report, is the most common cause of lower respiratory tract infections in infants and children.^7,8 Infection with this pathogen may lead to bronchiolitis or pneumonia. It has previously been recognized as a cause of serious disease in certain high-risk populations such as patients with lymphocyte immunodeficiencies, immunosuppressed children or adults, bone marrow transplant recipients, premature infants, and those with acquired pulmonary disease and congenital heart disease.⁹ In addition, RSV is a common nosocomial pathogen. Chest radiograph findings during acute infection may be normal or may show air trapping, peribronchial thickening, interstitial pneumonia, or segmental consolidation, the latter commonly attributable to atelectasis.¹⁰ Methods for the detection of RSV in the respiratory tract secretions include antigen detection by enzyme-linked immunosorbent assay, immunofluorescence, virus isolation in tissue culture, and reverse transcriptase polymerase chain reaction.^11,12 Treatment for RSV ranges from supportive care to aerosolized ribavirin.¹³ Prophylaxis with monoclonal antibodies and RSV immune globulin are now available and used in certain high-risk situations and populations.^13,14

	CASE PRESENTATIONS

Case 1

A boy with IFNR1 deficiency was diagnosed with disseminated Mycobacterium avium complex (MAC) at 8 months and treated with ethambutol, rifabutin, levofloxacin, azithromycin, and amikacin. At 3 years he developed disseminated cytomegalovirus with pneumonia, leading to intubation and intravenous ganciclovir. Subsequently he had parainfluenza III pneumonia, which was also complicated by respiratory failure. At 4 years of age, while being treated as an inpatient for his disseminated MAC infection, he developed respiratory distress after a brief period of upper airway congestion. He had rapid respirations (>60 breaths/minute), expiratory wheezing, and intercostal and substernal retractions. His oxygen saturation was <90% on room air. He was hypothermic but maintained adequate circulation. Chest radiograph and computed tomography (CT) showed a new left upper lobe density (Fig 1). Antigen detection assays for RSV and influenza in nasopharyngeal wash were negative. After intubation, RSV was confirmed in the bronchoalveolar lavage (BAL) by both rapid antigen detection and viral culture. MAC was also identified in the BAL fluid, but had been present before this episode and persisted afterward. He remained intubated for 7 days. He was treated with a prolonged course of nebulized ribavirin (14 days) and is currently maintained on prophylactic RSV immune globulin and palivizumab. Three weeks after the diagnosis of RSV pneumonia, follow-up CT scan of the chest showed clearance of the density.

View larger version (110K): [in this window] [in a new window]   Fig. 1.   CT scan of patient 1 showing a left lower lobe superior segment infiltrate (A). The same infiltrate not detected month before the onset of the RSV infection (B), or after antiviral treatment (C). The preexisting infiltrates on the right were mycobacterial infection, which is present in all 3 scans in the right lung.

View larger version (147K): [in this window] [in a new window]   Fig. 2.   CT scan of patient 2 showing right middle and lower lobe infiltrates and multiple areas of nodularity secondary to granulomatous disease.

View larger version (124K): [in this window] [in a new window]   Fig. 3.   CT scan of patient 3 showing a right lower lobe superior segment infiltrate.

Case 2

A 12-year-old boy was diagnosed with X-linked CGD at age 5. Aspergillus pneumonia at ages 4 and 5 led to right upper lobectomy and right lower lobe superior segment resections. He had recurrent sinusitis, skin infections, and oral and perirectal ulcers. Granulomatous colitis occurred at age 10, which responded to transient therapy with prednisone. He was maintained on itraconazole, trimethoprim-sulfamethoxazole and IFN at the standard CGD dose of 50 µg/m² 3 times weekly. He presented with several days of fevers, chills, and cough without wheezing. He had an elevated white blood cell count and an erythrocyte sedimentation rate of 38 mm/hour. Physical examination showed cervical lymphadenopathy and decreased breath sounds on the right, no rales or wheezing were appreciated. CT scan of the chest showed new right middle and lower lobe densities along with a preexisting nodularity (Fig 2). Culture of BAL yielded RSV. His infection resolved spontaneously and without sequelae.

Case 3

A 7-year-old boy with X-linked CGD diagnosed at 2 years of age had a history of granulomatous colitis, salmonellosis, staphylococcal liver abscess, pulmonary aspergillosis, and recurrent fungal skin infections. He was maintained on ciprofloxacin and prednisone 5 mg every other day. He developed fever, productive cough, congestion, runny nose, and bilateral ear pain 2 weeks before admission. The initial chest radiograph was normal and he was treated with oral antibiotics but continued to spike high fevers. On examination, his temperature was 38°C. He had clear nasal discharge, bilateral hyperemic and dull tympanic membranes and bibasilar rales right greater than left. Chest CT showed a right lower lobe superior segment infiltrate (Fig 3). RSV was detected in the nasopharyngeal secretions by rapid antigen detection assay and culture. His infection and the associated infiltrates and ear pain resolved spontaneously and without sequelae.

Methods Used for Antigen Detection and Viral Culture

Nasopharyngeal washes were obtained by trained respiratory therapists and processed within 2 hours. An indirect enzyme-linked immunosorbent assay (Directigen Becton Dickinson, Meylan, France) was performed on cell free supernatants to detect the RSV antigen. Multiple shell vial cultures of A549 (human lung carcinoma cell line) were inoculated by centrifugation and read at 24, 48 and 72 hours by immunofluorescent antibody.¹² An RSV specific monoclonal fluorescent antibody was used for immunofluorescent antibody staining.

	DISCUSSION

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We have described 3 patients with underlying phagocyte defects who developed RSV pneumonia diagnosed by viral detection assays of respiratory secretions in the setting of dense pulmonary infiltrates.

Although RSV is not usually suspected in CGD and patients with this primary immunodeficiency are not thought to be more predisposed to infection with RSV than the average pediatric population, it may present as dense or patchy infiltrates leading to a diagnostic dilemma. The apparent susceptibility to disseminated or severe viral infections in IFNR1 deficiency suggests that viral pathogens should be included in the differential diagnosis of acute infiltrates in children with IFNR defects in addition to mycobacterial infections. Consideration of RSV pneumonia in the differential diagnosis and detection of this virus in a timely manner prevented these patients from receiving unnecessary antibiotics and guided the use of specific antiviral treatment.

Gulbu Uzel, MD^*
Ahalya Premkumar, MD
Harry L. Malech, MD^*
Steven M. Holland, MD^*
* Laboratory of Host Defenses
National Institute of Allergy and Infectious Diseases
National Institutes of Health
 Department of Radiology
Warren Grant Magnuson Clinical Center
National Institutes of Health
Bethesda, MD 20892-1886

	FOOTNOTES

Received for publication Nov 1, 1999; accepted Feb 23, 2000.

Reprint requests to (S.M.H.) Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N103, 10 Center Dr MSC 1886, Bethesda, MD 20892-1886. E-mail: smh{at}nih.gov

	ABBREVIATIONS

RSV, respiratory syncytial virus; CGD, chronic granulomatous disease; IFNR, interferon- receptor; MAC, Mycobacterium avium complex; CT, computed tomography; BAL, bronchoalveolar lavage.

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