IFN-λ Diminishes the Severity of Viral Bronchiolitis in Neonatal Mice by Limiting NADPH Oxidase-Induced PAD4-Independent NETosis.

Infants with attenuated type III IFN (IFN-λ) responses are at increased risk of severe lower respiratory tract infection (sLRI). The IL-28Rα-chain and IL-10Rß-chain form a heterodimeric receptor complex, necessary for IFN-λ signaling. Therefore, to better understand the immunopathogenic mechanisms through which an IFN-λlo microenvironment predisposes to a sLRI, we inoculated neonatal wild-type and IL-28R-deficient (IL-28R -/-) mice with pneumonia virus of mice, a rodent-specific pneumovirus. Infected IL-28R -/- neonates displayed an early, pronounced, and persistent neutrophilia that was associated with enhanced reactive oxygen species (ROS) production, NETosis, and mucus hypersecretion. Targeted deletion of the IL-28R in neutrophils was sufficient to increase neutrophil activation, ROS production, NET formation, and mucus production in the airways. Inhibition of protein-arginine deiminase type 4 (PAD4), a regulator of NETosis, had no effect on myeloperoxidase expression, citrullinated histones, and the magnitude of the inflammatory response in the lungs of infected IL-28R -/- mice. In contrast, inhibition of ROS production decreased NET formation, cellular inflammation, and mucus hypersecretion. These data suggest that IFN-λ signaling in neutrophils dampens ROS-induced NETosis, limiting the magnitude of the inflammatory response and mucus production. Therapeutics that promote IFN-λ signaling may confer protection against sLRI.

The Contribution of Neutrophils to the Pathogenesis of RSV Bronchiolitis.

Acute viral bronchiolitis causes significant mortality in the developing world, is the number one cause of infant hospitalisation in the developed world, and is associated with the later development of chronic lung diseases such as asthma. A vaccine against respiratory syncytial virus (RSV), the leading cause of viral bronchiolitis in infancy, remains elusive, and hence new therapeutic modalities are needed to limit disease severity. However, much remains unknown about the underlying pathogenic mechanisms. Neutrophilic inflammation is the predominant phenotype observed in infants with both mild and severe disease, however, a clear understanding of the beneficial and deleterious effects of neutrophils is lacking. In this review, we describe the multifaceted roles of neutrophils in host defence and antiviral immunity, consider their contribution to bronchiolitis pathogenesis, and discuss whether new approaches that target neutrophil effector functions will be suitable for treating severe RSV bronchiolitis.

Elevated Levels of Type 2 Respiratory Innate Lymphoid Cells in Human Infants with Severe Respiratory Syncytial Virus Bronchiolitis.

Rationale: Studies of the immune responses at the site of respiratory syncytial virus (RSV) infection are sparse despite nearly five decades of research into understanding RSV disease.Objectives: To investigate the role of mucosal innate immune responses to RSV and respiratory viral load in infants hospitalized with the natural disease.Methods: Cytokines, viral load, and type 2 innate lymphoid cell (ILC2) levels in nasal aspirates, collected within 24 hours of enrollment, from infants hospitalized with RSV infection were quantified.Measurements and Main Results: RSV severity in infants was categorized based on admission to the general ward (moderate) or the pediatric ICU (severe). Evaluable subjects included 30 patients with severe and 63 patients with moderate disease (median age, 74 d; range, 9-297 d). ILC2s were found in the nasal aspirates of patients with severe disease (0.051% of total respiratory CD45+ cells) to a significantly greater extent than in patients with moderate disease (0.018%, P = 0.004). Levels of IL-4, IL-13, IL-33, and IL-1ß were significantly higher in nasal aspirates of patients with severe disease compared with those of patients with moderate disease. Factors associated with disease severity were gestational age (odds ratio, 0.49; 95% confidence interval, 0.29-0.82; P = 0.007) and IL-4 (odds ratio, 9.67; 95% confidence interval, 2.45-38.15; P = 0.001).Conclusions: This study shows, for the first time, that elevated levels of ILC2s is associated with infant RSV severity. The findings highlight the dominance of type-2 responses to RSV infection in infants and suggest an important role of ILC2 in shaping the immune response early during RSV infection.

LAIR-1 Limits Neutrophilic Airway Inflammation.

Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation induces immune pathology. The mechanisms by which neutrophils are regulated to prevent injury and preserve tissue homeostasis are not completely understood. We recently identified the collagen receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1 as a functional inhibitory receptor on airway-infiltrated neutrophils in viral bronchiolitis patients. In the current study, we sought to examine the role of LAIR-1 in regulating airway neutrophil responses in vivo. LAIR-1-deficient (Lair1-/-) and wild-type mice were infected with respiratory syncytial virus (RSV) or exposed to cigarette smoke as commonly accepted models of neutrophil-driven lung inflammation. Mice were monitored for cellular airway influx, weight loss, cytokine production, and viral loads. After RSV infection, Lair1-/- mice show enhanced airway inflammation accompanied by increased neutrophil and lymphocyte recruitment to the airways, without effects on viral loads or cytokine production. LAIR-1-Fc administration in wild type mice, which blocks ligand induced LAIR-1 activation, augmented airway inflammation recapitulating the observations in Lair1-/- mice. Likewise, in the smoke-exposure model, LAIR-1 deficiency enhanced neutrophil recruitment to the airways and worsened disease severity. Intranasal CXCL1-mediated neutrophil recruitment to the airways was enhanced in mice lacking LAIR-1, supporting an intrinsic function of LAIR-1 on neutrophils. In conclusion, the immune inhibitory receptor LAIR-1 suppresses neutrophil tissue migration and acts as a negative regulator of neutrophil-driven airway inflammation during lung diseases. Following our recent observations in humans, this study provides crucial in-vivo evidence that LAIR-1 is a promising target for pharmacological intervention in such pathologies.

New mouse model of pulmonary hypertension induced by respiratory syncytial virus bronchiolitis.

Pulmonary hypertension (PH) has been observed in up to 75% of infants with moderate to severe respiratory syncytial virus (RSV) bronchiolitis and is associated with significant morbidity and mortality in infants with congenital heart disease. The purpose of the present study was to establish a mouse model of PH secondary to RSV bronchiolitis that mimics the disease etiology as it occurs in infants. Neonatal mice were infected with RSV at 5 days of age and then reinfected 4 wk later. Serum-free medium was administered to age-matched mice as a control. Echocardiography and right ventricular systolic pressure (RVSP) measurements via right jugular vein catheterization were conducted 5 and 6 days after the second infection, respectively. Peripheral capillary oxygen saturation monitoring did not indicate hypoxia at 2-4 days post-RSV infection, before reinfection, and at 2-7 days after reinfection. RSV-infected mice had significantly higher RVSP than control mice. Pulsed-wave Doppler recording of the pulmonary blood flow by echocardiogram demonstrated a significantly shortened pulmonary artery acceleration time and decreased pulmonary artery acceleration time-to-ejection time ratio in RSV-infected mice. Morphometry showed that RSV-infected mice exhibited a significantly higher pulmonary artery medial wall thickness and had an increased number of muscularized pulmonary arteries compared with control mice. These findings, confirmed by RVSP measurements, demonstrate the development of PH in the lungs of mice infected with RSV as neonates. This animal model can be used to study the pathogenesis of PH secondary to RSV bronchiolitis and to assess the effect of treatment interventions. NEW & NOTEWORTHY This is the first mouse model of respiratory syncytial virus-induced pulmonary hypertension, to our knowledge. This model will allow us to decipher molecular mechanisms responsible for the pathogenesis of pulmonary hypertension secondary to respiratory syncytial virus bronchiolitis with the use of knockout and/or transgenic animals and to monitor therapeutic effects with echocardiography.

PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production.

Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

Interferon lambda receptor 1 (IFNL1R) transcript is highly expressed in rhinovirus bronchiolitis and correlates with disease severity.

BACKGROUND: As the expression of type III IFN receptor is restricted to the mucosal surfaces, its evaluation could be crucial to characterize the role of IFNλs during bronchiolitis. OBJECTIVES: This study was designed to investigate airway type III IFN receptor (IFNLR1/IL10RB) expression during respiratory syncytial virus (RSV) or human rhinovirus (HRV) bronchiolitis. STUDY DESIGN: Seventy-one 1-6 month old infants hospitalized with their first episode of acute RSV or HRV bronchiolitis were selected for this study. Expression of IFNLR1, IL10RB and IFN-stimulated genes (ISGs) MxA and ISG56 in cells of nasopharyngeal washings taken within the first 48 h of admission were determined by a real-time hydrolysis probe RT-PCR assay. The ability of types I and III IFNs to induce the expression of both IFNLR1 and IL10RB in vitro was also evaluated. RESULTS: Airway IFNLR1 transcript levels were significantly higher in HRV bronchiolitis infants compared to those with RSV bronchiolitis. No differences were recorded for IL10RB-mRNA between RSV or HRV infection. IFNLR1 mRNA levels increased significantly in infants infected with the C species of HRV and in those with a higher clinical score index and with an eosinophil count >3%. There were no correlations in vivo between type III IFN receptors and those of ISGs and neither IFNLR1 nor IL10RB were induced in vitro by IFNs. CONCLUSIONS: These results suggest that IFNLR1 are increased in HRV-infected infants with more severe bronchiolitis and blood eosinophilia and in those infected with the HRVC species.

Respiratory Syncytial Virus Genotypes, Host Immune Profiles, and Disease Severity in Young Children Hospitalized With Bronchiolitis.

Background: Data on how respiratory syncytial virus (RSV) genotypes influence disease severity and host immune responses is limited. Here, we characterized the genetic variability of RSV during 5 seasons, and evaluated the role of RSV subtypes, genotypes, and viral loads in disease severity and host transcriptional profiles. Methods: A prospective, observational study was carried out, including a convenience sample of healthy infants hospitalized with RSV bronchiolitis. Nasopharyngeal samples for viral load quantitation, typing, and genotyping, and blood samples for transcriptome analyses were obtained within 24 hours of hospitalization. Multivariate models were constructed to identify virologic and clinical variables predictive of clinical outcomes. Results: We enrolled 253 infants (median age 2.1 [25%-75% interquartile range] months). RSV A infections predominated over RSV B and showed greater genotype variability. RSV A/GA2, A/GA5, and RSV B/BA were the most common genotypes identified. Compared to GA2 or BA, infants with GA5 infections had higher viral loads. GA5 infections were associated with longer hospital stay, and with less activation of interferon and increased overexpression of neutrophil genes. Conclusions: RSV A infections were more frequent than RSV B, and displayed greater variability. GA5 infections were associated with enhanced disease severity and distinct host immune responses.

Respiratory Syncytial Virus Infects Regulatory B Cells in Human Neonates via Chemokine Receptor CX3CR1 and Promotes Lung Disease Severity.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. We analyzed the B cell compartment in human newborns and identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis.

Pooled Sequencing of Candidate Genes Implicates Rare Variants in the Development of Asthma Following Severe RSV Bronchiolitis in Infancy.

Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization.

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Rhinovirus infection in children hospitalized with acute bronchiolitis and its impact on subsequent wheezing or asthma: a comparison of etiologies.

BACKGROUD: Children who suffer a viral lower respiratory infection early in life are prone to subsequent wheezing and asthma: RSV and rhinovirus are thought to be the primary causative pathogens. Epidemiologic and long-term data on these pathogens in Thailand are limited. OBJECTIVES: To detect the causative pathogens in children hospitalized with a first episode of acute wheezing and to compare the respective impact on the recurrence of wheezing and development of asthma. METHOD: We conducted a 5-year cohort study of children under 2 hospitalized with acute bronchiolitis at two tertiary hospitals. Nasopharyngeal secretions were collected at admission to determine the causative pathogens by RT-PCR. RESULTS: 145/170 samples (85%) were positive for pathogens. RSV, rhinovirus, influenza, bacteria and hMPV was found in 64.7%, 18.2%, 17.6%, 12.9% and 3.5% of children respectively. The majority (94/152; 62%) of participants reported having recurrent wheezing within the first year of follow-up (mean duration 5.5 ± 7.2 months). Only 16% still had wheezing episodes after 5 years. Asthma was diagnosed in 41 children (45%), most of whom were treated with inhaled corticosteroid. There were no statistically significant differences among the various etiologies. CONCLUSION: Rhinovirus ranked second after RSV as the cause of hospitalizations of children with acute bronchiolitis. More than half of these children had recurrent wheezing which mostly disappeared before the age of 6. Nearly half were subsequently diagnosed with asthma at the 5th year of follow-up. The specific pathogens did not account for a statistically significant difference in subsequent wheezing or asthma development.

Mechanical ventilation drives inflammation in severe viral bronchiolitis.

INTRODUCTION: Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation. MATERIALS AND METHODS: Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL)-1α, IL-1ß, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α. RESULTS: Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1α, were elevated compared to non-ventilated infected controls: IL-1α (159 versus 4 pg/ml, p<0.01), IL-1ß (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05). CONCLUSIONS: Using pre- and post-intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis.

Viral bronchiolitis in young rats causes small airway lesions that correlate with reduced lung function.

Viral illness with wheezing during infancy is associated with the inception of childhood asthma. Small airway dysfunction is a component of childhood asthma, but little is known about how viral illness at an early age may affect the structure and function of small airways. We used a well-characterized rat model of postbronchiolitis chronic airway dysfunction to address how postinfectious small airway lesions affect airway physiological function and if the structure/function correlates persist into maturity. Brown Norway rats were sham- or virus inoculated at 3 to 4 weeks of age and allowed to recover from the acute illness. At 3 to 14 months of age, physiology (respiratory system resistance, Newtonian resistance, tissue damping, and static lung volumes) was assessed in anesthetized, intubated rats. Serial lung sections revealed lesions in the terminal bronchioles that reduced luminal area and interrupted further branching, affecting 26% (range, 13-39%) of the small airways at 3 months of age and 22% (range, 6-40%) at 12 to 14 months of age. At 3 months of age (n = 29 virus; n = 7 sham), small airway lesions correlated with tissue damping (rs = 0.69) but not with Newtonian resistance (rs = 0.23), and Newtonian resistance was not elevated compared with control rats, indicating that distal airways were primarily responsible for the airflow obstruction. Older rats (n = 7 virus; n = 6 sham) had persistent small airway dysfunction and significantly increased Newtonian resistance in the postbronchiolitis group. We conclude that viral airway injury at an early age may induce small airway lesions that are associated quantitatively with small airway physiological dysfunction early on and that these defects persist into maturity.

Signal inhibitory receptor on leukocytes-1 (SIRL-1) negatively regulates the oxidative burst in human phagocytes.

ROS production is an important effector mechanism mediating intracellular killing of microbes by phagocytes. Inappropriate or untimely ROS production can lead to tissue damage, thus tight regulation is essential. We recently characterized signal inhibitory receptor on leukocytes-1 (SIRL-1) as an inhibitory receptor expressed by human phagocytes. Here, we demonstrate that ligation of SIRL-1 dampens Fc receptor-induced ROS production in primary human phagocytes. In accordance, SIRL-1 engagement on these cells impairs the microbicidal activity of neutrophils, without affecting phagocytosis. The inhibition of ROS production may result from reduced ERK activation, since co-ligation of Fc receptors and SIRL-1 on phagocytes inhibited phosphorylation of ERK. Importantly, we demonstrate that microbial and inflammatory stimuli cause rapid downregulation of SIRL-1 expression on the surface of primary neutrophils and monocytes. In accordance, SIRL-1 expression levels on neutrophils in bronchoalveolar lavage fluid from patients with neutrophilic airway inflammation are greatly reduced. We propose that SIRL-1 on phagocytes sets an activation threshold to prevent inappropriate production of oxygen radicals. Upon infection, SIRL-1 expression is downregulated, allowing microbial killing and clearance of the pathogen.

Acute viral lower respiratory tract infections in Cambodian children: clinical and epidemiologic characteristics.

BACKGROUND: Viruses are detected in most hospitalized children admitted for acute respiratory infections. Etiologic understanding is needed to improve clinical management and prevention, particularly in resource-limited tropical countries. METHODS: A 3-year prospective descriptive study was conducted among Cambodian children admitted to 2 provincial hospitals for acute lower respiratory tract infection. Molecular detection for 18 viral pathogens using multiplex polymerase chain reaction/reverse transcription polymerase chain reactions was performed. RESULTS: We enrolled 1006 children less than 5 years of age of whom 423 (42%), 428 (42%) and 155 (16%) had pneumonia, bronchiolitis and unclassified lower respiratory tract infections, respectively. Of the 551 (55%) with documented viral infection, a single virus was detected in 491 (89%), including rhinovirus (n = 169; 34%), respiratory syncytial virus (n = 167; 34%), parainfluenza virus (n = 40; 8%), human metapneumovirus (n = 39; 8%), influenza virus (n = 31; 6%), bocavirus (n = 16; 3%), adenovirus (n = 15; 3%), coronavirus (n = 9; 2%) and enterovirus (n = 5; 1%). Coinfections with multiple viruses were detected in 6% (2 viruses detected in 59 cases; 3 viruses detected in 1 case). CONCLUSION: Similar to other tropical countries, rhinovirus and respiratory syncytial virus were the principal viral pathogens detected among children hospitalized for lower tract respiratory infection in Cambodia.

Pathogenesis of acute respiratory illness caused by human parainfluenza viruses.

Human parainfluenza viruses (HPIVs) are a common cause of acute respiratory illness throughout life. Infants, children, and the immunocompromised are the most likely to develop severe disease. HPIV1 and HPIV2 are best known to cause croup while HPIV3 is a common cause of bronchiolitis and pneumonia. HPIVs replicate productively in respiratory epithelial cells and do not spread systemically unless the host is severely immunocompromised. Molecular studies have delineated how HPIVs evade and block cellular innate immune responses to permit efficient replication, local spread, and host-to-host transmission. Studies using ex vivo human airway epithelium have focused on virus tropism, cellular pathology and the epithelial inflammatory response, elucidating how events early in infection shape the adaptive immune response and disease outcome.

Fatal adenoviral necrotizing bronchiolitis case in a post-cardiac surgery intensive care unit.

We report a case of a 67 year-old-male patient admitted to the intensive care unit in the post-coronary bypass surgery period who presented cardiogenic shock, acute renal failure and three episodes of sepsis, the latter with pulmonary distress at the 30th post-operative day. The patient expired within five days in spite of treatment with vancomycin, imipenem, colistimethate and amphotericin B. At autopsy severe adenovirus pneumonia was found. Viral pulmonary infections following cardiovascular surgery are uncommon. We highlight the importance of etiological diagnosis to a correct treatment approach.