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The contribution of non-SARS coronaviruses to acute lower respiratory tract disease in previously healthy children is unknown. Most pediatric coronavirus infections result in relatively mild upper respiratory tract illness, whereas these viruses have been associated with severe lower respiratory tract diseases (eg, bronchiolitis and pneumonia) in children with high-risk medical conditions, such as those with asthma, immunosuppression, or significant prematurity.1–3 Improved methods of viral discovery have facilitated the recent identification of 2 novel group 1 and 2 human coronavirus subtypes—NL63 and HKU1—and a more accurate clinical epidemiology of coronavirus infection is beginning to emerge.4,5 However, it remains unclear to what extent coronaviruses are associated with lower respiratory tract disease in previously healthy children without underlying illnesses. Few data have been presented on the subject, and the full clinical course and outcome of a previously healthy child with coronavirus-associated pneumonia has not yet been detailed in the literature.
We investigated instances of radiographically confirmed lower respiratory tract disease in previously healthy children with coronavirus infection. From a group of 56 coronavirus-positive children of 828 children who presented with respiratory symptoms to a tertiary-care hospital during a 1-year period6 we retrospectively identified those who (a) were previously healthy without any evidence of underlying pulmonary, cardiac, renal/hepatic, or central nervous system disease, immunosuppression, or history of prematurity, (b) had only coronavirus present in their respiratory specimen as detected by reverse transcription polymerase chain reaction (RT-PCR) assays6,7 of 14 respiratory viruses, including respiratory syncytial virus (RSV), adenovirus, influenza viruses A and B, parainfluenza virus (PIV) types 1–4, human metapneumovirus (hMPV), rhinovirus, and all 4 non-SARS coronavirus subtypes, and (c) had a chest radiograph obtained within 24 hours preceding or after their positive respiratory sample.
Twenty-one children had an isolated coronavirus infection and chest radiograph. Most (81%) had underlying medical conditions. Four children met all 3 of the above criteria and 2 (50%) had radiographic evidence of pneumonia as confirmed by a pediatric infectious disease specialist and 2 independent radiologists; 1 read the films in real time and had limited knowledge of the clinical findings, and 1 read the films retrospectively and had no knowledge of the clinical findings. Here we describe the clinical courses of these 2 previously healthy children.
CASE STUDY 1
A 14-month-old previously healthy girl was admitted to the hospital for respiratory distress and evaluation of an abnormal chest radiograph after 5 days of fever, runny nose, and nasal congestion. Before admission, she was evaluated 3 times: twice by her primary physician who diagnosed her with a viral URI and conjunctivitis, and once in the emergency room (ER) at a local community hospital where she had a chest radiograph, which was abnormal. In this interval she received only antimicrobial eye-drops. On day 6 of illness she developed a cough, posttussive emesis, and poor oral intake, and was taken to the ER at Children's Hospital and Regional Medical Center.
At admission, she had 96% oxygen saturation on room air and decreased breath sounds on the right side. A chest radiograph demonstrated a large, relatively lucent, rounded shadow with sharp borders in the right posterior mediastinum (Fig. 1A, Chest Radiograph—Right Mediastinal Opacity; available online). Laboratory findings were significant for a leukocytosis (white blood cell count of 17,800/mm3 with 27% bands) and an elevated erythrocyte sedimentation rate (55 seconds). She was then admitted and treated empirically with intravenous cefuroxime. A follow-up computed tomography scan of her chest showed consolidation of the posterior and superior segments of the right lower lobe, with surrounding ground glass opacities (Fig. 1B, CT Scan—Right Lower Lobe Consolidation; available online).
Her nasal wash specimen was negative on florescent antibody assays for multiple respiratory viruses, including RSV, adenovirus, influenza viruses A and B, and PIV types 1–3, and later the specimen was found to be negative on RT-PCR6,7 for the above viruses and additionally for rhinovirus, PIV type 4, hMPV, and coronavirus subtypes 229E, NL63, and HKU1. Coronavirus subtype OC43 was the sole viral respiratory pathogen detectable by RT-PCR of her original nasal wash specimen. Bacterial cultures of her blood remained negative.
The patient's clinical course was uncomplicated. She had a mild fever of 38.2°C on the first day of admission, but improved throughout the rest of her hospitalization, remaining afebrile without an oxygen requirement. She was discharged on hospital day 3 to complete a 10-day course of oral cefuroxime.
CASE STUDY 2
A 3-month-old previously healthy boy was admitted to the hospital with fever, respiratory distress, and radiographic evidence of pneumonia after 7 days of acute coryza and progressively worsening respiratory symptoms. Before admission, he presented multiple times to the ER and was given amoxicillin when a chest radiograph revealed an early right lower-lobe pneumonia. Despite this therapy, he had increased work of breathing, culminating in an episode of cyanosis that lasted several minutes and prompted admission to Children's Hospital and Regional Medical Center.
On initial examination, the patient had a temperature of 38.0°C, a significantly elevated white blood cell count of 27,800/mm3, and an oxygen saturation of 89% for several minutes, which responded to supplemental oxygen. Lung examination was notable for scattered rhonchi and mild subcostal retractions, and a chest radiograph showed diffuse interstitial infiltrates and a right-sided pleural effusion (Fig. 2 Chest radiograph of coronavirus-associated pneumonia with right pleural effusion in Case Study 2; available online). Despite intravenous fluids and antibiotics (cefuroxime), he continued to develop increased work of breathing with mild desaturations (94%–97%) and inadequate perfusion. He then became febrile (39.1°C) and was transferred to the infant intensive care unit for closer monitoring. There, he had intermittent fevers and received nebulized albuterol therapy and oxygen as required, but his pulmonary status remained relatively stable overall. A subsequent chest radiograph showed a reduced pleural effusion without significant infiltrates. He was transferred back to the general pediatric ward on the third day of admission and there he remained afebrile, was weaned off supplemental oxygen, and was discharged home on oral cefuroxime.
Immunofluorescence and RT-PCR assays of this patient's nasal wash specimen were negative for all respiratory viruses described previously, and multiple blood cultures remained negative through 5 days. The newly described coronavirus subtype HKU1 was the only viral respiratory pathogen detectable by RT-PCR analysis of his nasal wash specimen.
DISCUSSION
In these 2 cases, retrospective analysis by RT-PCR confirmed an association between coronavirus infection and radiographically confirmed pneumonia in children without underlying illnesses, immunosuppression, or a history of prematurity. Both children were the result of normal term pregnancies, and both were previously healthy without underlying medical conditions. Coronavirus subtypes OC43 and HKU1 were the only viral pathogens detected by RT-PCR in their respiratory specimens; microbiologic cultures of blood from both patients remained persistently negative. Although negative results of bacteriologic cultures cannot exclude a bacterial origin in these cases, especially given the fevers and hematologic findings noted during the acute phase of their illnesses, the detection of coronavirus as the sole viral respiratory pathogen in nasal wash specimens from these children is important. We speculate that coronavirus subtypes may play a pathogenic role in lower respiratory tract disease—either alone or with a bacterial copathogen—even among previously healthy children.
Recently in South Africa, a large randomized controlled trial of a 9-valent pneumococcal conjugate vaccine demonstrated a significant reduction in bacterial pneumonias8 and in pneumonias attributed to respiratory viruses.9,10 These studies argue that infection with hMPV10 and other common respiratory viruses such as RSV, influenza A, and PIV types 1–39 may predispose children to bacterial pneumonias. No such data exist for coronavirus infection.
Shortly after the discovery of coronavirus in the late 1960s, this novel pathogen was found to account for a portion of previously unexplained respiratory disease in children. Using serologic methods, McIntosh et al11 demonstrated rising antibody titers to group 1 coronavirus subtype 229E and group 2 subtype OC43 in 7.9% of 380 serum samples collected from infants (<18 months of age) hospitalized with pneumonia or bronchiolitis between 1967 and 1970. The prevalence of underlying illnesses among infected children was not reported in this study. Recently, more sophisticated viral detection methods have enabled the identification of 2 novel human coronavirus subtypes—NL63 (group 1) and HKU1 (group 2).4,5 Several studies have now more accurately characterized the spectrum of acute clinical illnesses associated with coronavirus infection,4,5,12–14 but clinical information on coronavirus-associated lower respiratory tract disease among previously healthy children remains limited.
In a study from Hong Kong by Chiu et al13, 26 of 587 hospitalized children had coronavirus NL63, OC43, or 229E detected from respiratory specimens by RT-PCR. Seven patients without underlying conditions had NL63 as the sole pathogen detected, and only 3 showed evidence of lower respiratory tract disease. All 3 had cough and stridor, did not have chest radiographs documented, and were diagnosed with croup. Of the 4 previously healthy children with only OC43 detected, 1 child had a radiographically confirmed lower-lobe infiltrate13. Similarly, Esper et al14 examined specimens from 851 children to identify 9 with HKU1 as the sole respiratory pathogen as determined by direct immunofluorescence for influenza, PIV types 1–3, RSV, and adenovirus, and by RT-PCR for hMPV and coronavirus subtypes HKU1 and NH (an NL63-like coronavirus subtype). They documented 2 previously healthy HKU1-infected children with radiographic evidence of pneumonia. Although these 2 children did not have further RT-PCR testing for respiratory viruses, which may be more sensitive than direct immunofluorescence assays,7,15 these data are consistent with our findings that lower respiratory tract disease may be associated with coronavirus infection in previously healthy children without underlying conditions.
Although historically considered a benign pathogen responsible for common colds, coronavirus is associated with more severe respiratory illnesses in the presence of predisposing risk factors. We have demonstrated here that coronavirus may also play a pathogenic role—either alone or possibly with a bacterial copathogen—in lower respiratory tract disease among children without underlying cardiopulmonary disease, immunosuppression, or a history of prematurity. The cases described in this report provide a clinical description of radiographically confirmed coronavirus-associated pneumonia in previously healthy children. Additionally, study of case 2 illustrates that coronavirus-associated pneumonias can have significant clinical consequences, resulting in infant intensive care unit admission even among children without chronic underlying health issues. We note that both subjects in this report received long-term empiric intravenous and oral antibiotics. As the contribution of coronavirus and other newly identified respiratory viruses to the overall burden of disease in young children is elucidated, a rapid and sensitive diagnostic test for detection of these viruses and for potential bacterial copathogens may ultimately provide an important means of decreasing use of antibiotics in children with viral pneumonia.
ACKNOWLEDGMENTS
The authors thank Michael Boeckh for thoughtful review of this manuscript.
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