Dataset: 11.1K articles from the COVID-19 Open Research Dataset (PMC Open Access subset)
All articles are made available under a Creative Commons or similar license. Specific licensing information for individual articles can be found in the PMC source and CORD-19 metadata.
More datasets: Wikipedia | CORD-19
Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
Funded by The Federal Ministry for Economic Affairs and Energy; Grant: 01MD19013D, Smart-MD Project, Digital Technologies
It has been recommended that treatment or prevention of a viral disease may be a superior method for diminishing of complications from influenza.84,85 Since viral infections might lead to secondary bacterial infection, it is prudent to vaccinate patients with the influenza vaccine to diminish the risk of OM in children and pneumonia in adults.62
It has also been published that live attenuated influenza vaccine is effective in reducing the incidence of all-cause AOM86–88 and pneumonia89 compared to placebo in children. In addition, the intranasal influenza vaccine can reduce OM by 44%.90 Moreover, studies have shown that a combined influenza/pneumococcal vaccine is efficient in the prevention of OM in children and pneumonia.91,92 However, the credit of protection was awarded to the influenza vaccine since studies have shown that pneumococcal vaccine has no benefit in the reduction of AOM.93,94 In addition, the pneumococcal polysaccharide vaccine showed no efficacy in the prevention of pneumonia in adults.95
Treatment of viral infection is anticipated to prevent bacterial superinfections. Currently, the only respiratory virus that is pharmacologically treatable is the influenza viruses (Type A and B).62 Neuraminidase inhibitors can potentially diminish the morbidity related to influenza.96 Oseltamivir can reduce the incidence of AOM in preschool children,97 and the reduction rate can be up to 44%.98 A meta-analysis review showed that oral oseltamivir reduces the rate of hospitalization by 25% and morbidity by 75%.99 In addition, its use can reduce the use of antibiotics by up to 50%,100,101 The same concept of protection applies to vaccines that prevent against RSV infections.62 The vaccine available for RSV is palivizumab (MedImmune, Gaithersburg, MD, USA), a humanized monoclonal antibody that perceives the fusion protein of RSV. The other monoclonal antibody that is under clinical trials is motavizumab (MedImmune), which has a higher affinity for RSV fusion protein than palivizumab and can prevent against medically attended lower respiratory tract infection.102
The majority of patients with asthma had viral and bacterial pathogens contributing to their disease. Regular surveillance could play a role in asthma care, especially in those with poorly controlled disease. Effective strategies to minimize exposure to respiratory pathogens, such as hand hygiene should be incorporated in childhood asthma guidelines. Such approach would emphasize the importance of environmental control measures rather than relying solely on escalating asthma drug therapy with its potential toxicity. Further studies are needed to evaluate whether strategies that minimize children’s exposure to pathogens would improve asthma control.
The rate of concurrent serious bacterial infections with viral illness is appreciable. Similar emphasis must be given to the prevention and treatment of viral illnesses, especially in young children. Furthermore, health care providers should emphasize to parents on the importance of clinical follow-up of infants and young children diagnosed with VRTI. Moreover, the introduction of MxA in the diagnosis of viral illnesses in children is promising.
Knowing which patients with LRTIs to treat and not to treat is challenging to determine, and physicians often err on the side of caution and prescribe antibiotics, given the high mortality rates of some bacterial LRTIs often without diagnostic results. Most patients are then empirically treated with antibiotics to pre-emptively avoid severe complications from bacterial LRTIs.
Improved diagnosis of the etiology of these infections would enable targeted therapy, leading to an overall more judicious use of antibiotics, which would likely decrease the rate of antimicrobial drug resistance as well as the safety impact of inappropriate treatment modalities on the patient. Due to the improper treatment of LRTIs, some infected patients may not be treated adequately because the responsible bacterium (such as S. pneumoniae, methicillin-resistant S. aureus and Gram-negative bacilli) is resistant to available antibiotics, leaving physicians without a weapon to combat the illness. The prudent use of available antibiotics in patients and animals, giving them only when needed, with the correct diagnosis and etiologic understanding, and in the correct dosage, dose intervals and duration is imperative. Antimicrobial stewardship is based on this premise. Over 262 million courses of outpatient antibiotic therapy were prescribed in 2011 with half of those antibiotics being unnecessary. The most inappropriate use is for acute respiratory infections, including acute bronchitis. Further research into rapid, patient-friendly, inexpensive, and accessible diagnostic modalities to appropriately characterize LRTIs as bacterial versus viral versus other is necessary to harness antibiotic use. In addition, determination of the causative bacterial pathogen will further antibiotic stewardship programs, lowering the risk of propagating resistance and unwanted adverse events including the development of C. difficile. The advancements noted above are certainly moving in the right direction to understanding the etiology of pneumonia in a rapid manner, but development still continues for even faster, more comprehensive testing.
ARIs are extremely common in children, especially those under 5 years old. They can lead to complications, super-infection, respiratory failure, and even compromised respiratory function in adulthood. For some of the responsible pathogens, vaccines are available. This review focuses on the most recent data about vaccines against respiratory pathogens. The use of influenza, pneumococcal, pertussis and measles vaccines is essential to reduce ARIs burden. Vaccination coverage rates must be improved to achieve the full benefits of these vaccines. Recently, advances in the knowledge of RSV virus biology and immunology as well as the development of new techniques to generate vaccine candidates are finally increasing the number of promising vaccines against even this harmful pathogen.
Although dependent on provider judgment, patients with mild to moderate disease can be safely discharged home to undergo antibiotic treatment, with careful attention noted to household contacts or other possibly exposed individuals. Hospital admission is recommended for neonates because they are at risk for apnea.19 Additionally, admission is recommended for patients
The Science and Bioethics Committee of the INER revised and approved the protocol and the consent procedure (B2613). For all pediatric patients, the corresponding legal guardians provided written informed consent.
Suctioning and other airway management is a mainstay of management. As with other conditions, in the presence of hypoxia or respiratory distress, supplemental oxygen should be applied. Intravenous fluids may also be needed for treatment of dehydration.19,23 In addition to supportive care, antimicrobial treatment is recommended. Macrolides are the preferred treatment, which include azithromycin, clarithromycin or erythromycin. 19,23,24 For infants
PEP is limited to certain groups (Table).25 These include household contacts of a pertussis case and high-risk populations. With regard to household exposures, even if these contacts are asymptomatic and/or current with immunizations, it is recommended they receive antimicrobial treatment within 21 days of cough onset in the index patient. High-risk groups include infants, women in their third trimester of pregnancy, caregivers or household contacts of infants, and anyone who works in or attends a childcare setting.25 Antibiotic selection and duration of treatment for either PEP or a confirmed case of pertussis are identical. Depending on the patient’s age and therapy of choice, treatment includes a 5–14 day course of a macrolide, with the treatment duration dependent on the macrolide chosen. In cases of PEP, treatment should be initiated within 21 days of exposure.19, 23
A total of 50 out of the 61 patients received antiviral or antibacterial treatment during hospitalization. Oseltamivir treatment was initiated in 19 patients awaiting test results, of which five tested positive for influenza A. In the 14 influenza ePlex® RP panel negative patients, oseltamivir could have been stopped approximately one day earlier (median of 22.59 h, range 5.33–72.03) based on the ePlex® RP results compared to LDT (Table 6). Of the total of 11 patients who tested influenza positive, the remaining six did not receive oseltamivir at the time of diagnosis. In one patient, oseltamivir treatment was started as soon as the ePlex® RP panel showed influenza A, one day prior to the LDT results, and one patient started when LDT was positive. Four patients did not receive any antiviral treatment, of which two were already dismissed at the time of definite LDT diagnosis.
Awaiting test results, 19 patients received antibiotic treatment for bacteria causing atypical pneumonias. In none of these patients, either the ePlex® RP panel or LDT (eight were tested) was positive for Bordetella pertussis, Legionella pneumophila, and Mycoplasma pneumoniae. In theory, in these 19 patients, a median duration of 23.35 h (range 0.43–75.28) antibiotic treatment for atypical pneumonia could have been saved, if treatment was stopped when the ePlex® RP panel tested negative.
The primary endpoint evaluated was in-hospital mortality. Secondary endpoints included hospital length-of-stay (LOS), intensive care unit (ICU) admission, and readmission rates at 30, 90, and 180 days after the index hospitalization.
Antibiotics treat LRTIs with a bacterial etiology. With the potential for antibiotic-resistant bacteria as well as sequelae from the use of unnecessary antibiotics including Clostridioides difficile infection, defining the etiology of the LRTI is imperative for appropriate patient treatment. Currently, there are few diagnostic tools to adequately do this in a time-efficient manner at the point of care.
Clinical assessment does not typically decipher between bacterial, viral or both as an etiology for LRTIs. Therefore, diagnostic tools are essential for empiric treatment. Currently, these tools include the use of C-reactive protein, procalcitonin, and/or other combinations.
Briefly, C-reactive protein (CRP) is an acute phase reactant synthesized by the liver in response to cytokines, such as interleukin-6, released by macrophages and adipocytes in response to inflammatory conditions from bacterial infections. Consortia have developed interpretative cut-offs for CRP levels to assist physicians with antibiotic prescribing. CRP levels ≤ 20 mg/L indicate a self-limited LRTI for which antibiotics are not needed, and CRP ≥ 100 mg/L indicate severe infection for which antibiotics should be prescribed. CRP levels between 21 and 99 mg/L are more challenging to interpret and must include further clinical assessment (Table 1).
Although rapid tests for CRP are used in point-of-care settings, the use of CRP has been controversial. A Cochrane review of trials conducted throughout Europe and Russia determined that CRP levels may reduce the use of antibiotics but the results did not affect patient outcomes, and suggested that increased hospitalization due to CRP evaluation may occur. Although Andreeva et al. reports a decrease of 36% in antibiotic prescribing with the evaluation of CRP, the authors discuss multiple studies that have not resulted in such changes. Therefore, the utility of CRP levels remains specific to individual treatment settings, and the measurement of CRP is not a substitute for clinical assessment and follow-up, which remain main-stays in the assessment of LRTIs.
For HAP/VAP, Infectious Diseases Society of America (IDSA) has indicated that clinical criteria alone, rather than using CRP is preferred, since CRP results did not reproducibly determine whether VAP was bacterial, leaving clinicians to rely on clinical assessment alone. Procalcitonin (PCT) is another acute phase reactant associated with bacterial infections. PCT increases within 2–4 h of infection, peaking at 24–48 h. PCT is used to assist in the diagnosis of sepsis and has since been used for LRTIs and post-operative infections. Like CRP, its use has been targeted to ensure appropriate antibiotic use (Table 1). Typically, PCT is produced by parafollicular cells of the thyroid and by the neuroendocrine cells of the lung and the intestine in small quantities and is a precursor to calcitonin which regulates calcium and phosphate in the blood, but bacterial endokines and cytotoxins stimulate its production early in the disease process. Evidence has shown that PCT is a useful method in guiding the initiation and duration of antibiotic treatment for LRTIs. A meta-analysis of 32 randomized studies with a majority of patients with acute LRTIs showed that PCT testing lowered mortality (decrease of 1.4%), antibiotic consumption (2.4 day mean reduction in exposure), and antibiotic-related adverse events (decrease of 5.8%). Briel et al. evaluated 458 patients whom the physician thought needed antibiotics for a respiratory tract infection. Patients were randomized to PCT-guided approach to antibiotic therapy or to a standard approach. The antibiotic prescription rate was 72% lower in those who had procalcitonin-guided antibiotic use without any impact on patient outcome. However, Huang et al. conducted a study in 14 hospitals in the United States and among 1656 patients observed no significant difference between the PCT group and the usual-care group in antibiotic days (mean, 4.2 and 4.3 days, respectively) or the proportion of patients with adverse outcomes (11.7% and 13.1%, respectively). The bioMérieux’s VIDAS® BRAHMS PCT™ test has been developed and was approved by FDA in 2017 to differentiate bacterial from viral infections and ultimately whether antibiotics are needed for pneumonia (Table 1). An ongoing study (Targeted Reduction of Antibiotics using Procalcitonin; TRAP-LRTI) is evaluating outpatient adults with suspected LRTIs and low procalcitonin levels. Low blood levels of PCT (≤0.25 ng/mL) using bioMérieux’s VIDAS® BRAHMS PCT™ test, which produces results within 20 min, is being used as an inclusion criterion, and then patients will be randomized to either azithromycin for 5 days or placebo. At Day 5, patients will be evaluated for improvement in symptoms with additional follow-up to 28 days after randomization. The study will evaluate the recovery of patients given azithromycin versus placebo, and whether a low PCT level can be used to avoid antibiotic therapy. The study will be completed in 2020, and it will add evidence to the utility of point-of-care PCT testing for patients with symptoms of LRTI in the outpatient setting.
Using host biomarkers in conjunction has also been studied and found to have high sensitivity and specificity for bacterial LRTIs. A point-of-care test of CRP and Myxovirus resistance protein A (MxA) was used in 54 patients with pharyngitis or LRTIs to determine the etiology of the infection. This combination characterized 80% (16/20) with bacterial infection, 70% (7/10) with viral infection, along with 92% (22/24) negative for a bacterial or viral infection. However, this study was small, and further confirmation of this point of care test is needed. Another host-protein signature assay combines the results of tumor necrosis-factor related apoptosis-inducing ligand (TRAIL), interleukin-10, and CRP and produces a score of 0–100 using the ImmunoXpert™ software. ImmunoXpert™ scores of <35 indicate nonbacterial etiology, whereas scores of ≥65 predict bacterial infections including mixed viral/bacterial co-infections. This assay has a sensitivity of 93% with a 91–94% specificity. The use of this assay was superior to using the biomarkers individually, so development is continuing for a point-of-care platform to provide results within 15 min.
Verbal consent was obtained from parents/legal tutor and subjects before screening to determine eligibility. Once a patient was determined to be eligible for study participation, written informed consent and assent (for children older than 8 years) were obtained. The protocol was approved by the institutional review board of each hospital.
A 76-year-old Caucasian man who underwent laryngectomy 10 years earlier, presented with fever (38.9 °C; 102.0 °F), increased sputum production, and purulent conjunctivitis. These symptoms emerged gradually over a period of 48 hours. He noted increasing difficulty in coughing out his sputum that became brownish and viscous. He had been wearing a heat and moisture exchanger (HME) filter that covered his stoma and spoke through a tracheoesophageal voice prosthesis. The symptoms started a day after a very cold weather spell with temperatures of −7 to −1 °C (19–31 °F). He had to remove his HME on several occasions for extended periods of time to enable him to breathe when he walked outside his home.
His past medical history included hypopharyngeal squamous cell carcinoma which was treated with intensity-modulated radiotherapy (IMRT) 12 years earlier. A recurrence of the cancer 2 years later required laryngectomy. He had no signs of tumor recurrence since then. He also suffered from paroxysmal hypertension, diverticulitis, and migraines.
He was vaccinated with the current Influenza virus vaccine 3 month earlier. He had also received a pneumococcal polysaccharide vaccine (PPSV23) 2 years earlier.
He was in mild respiratory distress especially when coughing. He had coughing spells and expectorated green-brown dry and viscous sputum. A physical examination revealed bilateral purulent conjunctivitis and auscultation of his lungs revealed coarse rhonchi and no crepitations. No lymphadenopathy was noted. The results of the rest of the physical and neurological examinations were within normal limits. A chest X-ray was normal.
Sputum and conjunctival culture grew heavy growth of beta-lactamase-producing nontypeable Haemophilus influenzae (NTHi) that was susceptible to levofloxacin and amoxicillin- clavulanate. A FilmArray® Respiratory Panel 2 (RP2) polymerase chain reaction (PCR) system test did not detect 14 viruses (adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human rhinovirus/enterovirus, human metapneumovirus, influenza A, influenza B, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, respiratory syncytial virus) and four bacteria (Bordetella pertussis, Bordetella parapertussis, Chlamydophila pneumoniae, Mycoplasma pneumoniae).
He was treated with orally administered levofloxacin 500 mg/day, ciprofloxacin eye drops, acetaminophen, and guaifenesin. Humidification of his trachea and the airway was maintained by repeated insertions of 3–5 cc respiratory saline into the stoma at least once an hour and by breathing humidified air.
The main challenge was to maintain a patent airway as the mucus was very dry and viscous and tended to stick to the walls of his trachea and the stoma. The mucus had to be repeatedly expectorated by vigorous coughing and by manual removal from the upper part of his trachea and stoma.
He experienced repeated episodes of sustained elevated blood pressure (up to 210/110) and tachycardia (112/minute). This was managed by administration of clonidine 0.1 mg as needed (1–2/day).
His fever started to decline 48 hours after antimicrobial therapy was started. The conjunctivitis improved within 36 hours. The sputum production declined and became less viscous over time, but persisted for 5 days.
Antimicrobial therapy was discontinued after 7 days.
His condition improved and he had a complete recovery in 7 days. He was seen in the clinic every 2 months and showed no recurrence of his infection for the following 8 months. He received vaccination for H. influenzae B and Prevnar 13® (pneumococcal conjugate vaccine; PCV13) 4 weeks after his recovery.
Since 2009, real-time reverse transcriptase–polymerase chain reaction (RT-PCR) for detection of Bordetella pertussis was performed on nasopharyngeal and/or tracheal secretions for all patients admitted with suspected pertussis or bronchioltis.
Suspected pertussis symptoms were consistent with the World Health Organization (WHO) definition case.4
Nasopharyngeal secretions (NPS) obtained by aspiration on sterile tubes were the specimens of choice for Bordetella detection by culture and/or quantitative real-time polymerase chain reaction (qPCR). Tracheal samplings were also accepted. Time from specimen collection to receipt in the laboratory was 20 min to 2 days, with no transport additives. The RT-PCR targets include the IS481, commonly found in B. pertussis, B. bronchiseptica, and B. holmesii; the IS1001, specific of B. parapertussis, in combination with the pertussis toxin promoter region gene (ptx) of B. pertussis; and the recA gene-specific of B. holmesii. NPS and/or tracheal sampling for viral detection through RT-PCR were also performed in all infants. We reviewed the medical charts of 17 children [median age 56 days (range 24–630); sex-ratio: 0.88] admitted to our PICU between 01 January to 31 October 2013 for confirmed CP by RT-PCR. Only mechanically ventilated patients were included.
Clinical data included: patient demographics, neonatal history, immunization status, presentation. Routine laboratory data and chest radiographs were also performed at admission in order to reveal infiltrate or consolidation imagings. Severity of Pediatric Risk of Mortality Score (PRISM) was evaluated at the time of PICU admission. During the hospitalization, the presence of complications and coinfections with viral or bacterial pathogens were checked, and all therapeutic interventions, including duration of respiratory or circulatory support with or without sedation, muscle paralysis, inhalation of nitric oxide were recorded.
Extracorporeal Membrane Oxigenation (ECMO) treatment was not available in Children’s Hospital Béchir Hamza PICU.
Based on the outcome, we divided subjects on two groups “survival” and “deaths” and we studied risk factors for poor outcome.
A prospective, multicenter, observational study was conducted between January 2009 and September 2011. Three hospitals participated in the study: Seoul St. Mary's hospital; Suwon St. Vincent's hospital; and Incheon St. Mary's hospital. We evaluated all infants clinically suspected of pertussis infection because of a cough lasting at least 2 weeks with at least one of the following symptoms: paroxysmal coughing; inspiratory whooping; post-tussive vomiting or apnea without other known cause. We obtained information on current respiratory manifestations, radiologic findings and immunization status for each infant. Diagnostic approaches for pertussis were conducted for clinical cases. Nasopharyngeal aspirates (NPA), or swab samples if aspirates were not possible, and blood samples were collected within 2 days at admission. Laboratory tests were performed at the Vaccine Bio Institute (VBI) of The Catholic University of Korea. It is determined as the criteria for laboratory-confirmed pertussis case when the subjects is applicable to one of the following criteria: 1) positive result of B. pertussis on culture of nasopharyngeal aspirates (NPA) or swab; this sample was collected and cultured on Regan-Lowe culture medium at 37℃ for more than 1 week; 2) positive result of B. pertussis in PCR or real-time PCR (RT-PCR) of NPA or swab; PCR was done by the method Glare et al. reported (16), and RT-PCR was done by modified method of Reischl U. Colleagues manual (17); 3) positive serology which defined as pertussis toxin (PT) antibody in a single serum sample that was higher than cut-off value (24 EU/mL) of enzyme-linked immunosorbent assay (ELISA) kit (IBL, Hamburg, Germany) or a 4-fold increased change in anti-PT antibody between acute-phase and convalescent-phase serum.
After the laboratory confirmation on pertussis, the parent or legal guardian for registration of index case was contacted as soon as possible, and all infants who are eligible for inclusion criteria were registered to the study immediately upon receipt of the consent form. To all family members if cough started at least 7 days before the onset of symptoms in the index case, it was requested to participate in the study as household contacts. And they were registered for the study immediately upon receipt of the consent form, and interviewed using the standard questionnaire to collect demographic and clinical data. Also, for all long-term household contacts, it was asked to visit for the study to collect respiratory samples (for culture, PCR, RT-PCR identification of B. pertussis) and/or serum samples (for ELISA).
A total of 17 children were included. Fifty two per cent of the enrolled patients were female. Demographics and illness history are summarized in table 1. Median age at admission was 56 days (range 24–630) and nine patients were under 2 months of age. Month distribution is displayed in figure 1. Median PRISM was 12 (IQR 4–27). Twelve patients (71%) were unimmunized. Five had received only one dose of pertussis vaccine and were partially immunized. The source of infection was identified in 9 (53%) cases. Mother-to-infant transmission occurred in six cases (66%).
Clinical presentation on admission showed repeated cough with desaturation and bradycardia in 15 patients (88%), apnea in 1 patient (6%) and hypoxia in 8 patients (47%). Six patients (35%) had no respiratory distress when coughing stopped. Tachycardia more than 200 bpm was present in five cases (29%), shock in 4 cases (23.5%), seizures in 6 cases (35%), and altered mental states in 3 cases (17.6%). Among patients where an echocardiogram was done, 2 patients had pulmonary hypertension. Echocardiography was done on 4 patients.
Median initial WBC was 41 × 109 L–1 (IQR 3.8–125.109). Initial WBC counts greater than 100 × 109 L–1 was reported in all deaths. Chest radiograph on admission identified pneumonia in 14 patients (82%) and was normal in only 3 cases(17.6%). Based on blood gases, seven patients had PaO2/ FiO2 <200.
Viral studies were available in 15 subjects (88%). Eight patients (53%) had viral coinfection with Rhinovirus in 7 cases and with Rhinovirus and Coronavirus in only one case. Two among 4 deaths had coinfection with rhinovirus. Viral coinfection was not related to mortality in our study.
All patients required mechanical ventilation. Intubation was done immediately at PICU admission for 15 cases and after a median delay of 2 days of non invasive ventilation for the others. The median duration of ventilation in survivors was 9 days (IQR, 3–20 days).
The indications for intubation were: cyanogenic cough in 11 patients (64%), severe hypoxic respiratory failure in 4 cases (23%), septic shock in one case (6%) and encephalopathy in the last case (6%). High frequency ventilation was performed in one patient (6%). All patients received fentanyl and midazolam sedation and only 2 patients (12%) were treated with muscles paralysis.
Four patients (23 %) received inotropes and 2 (11.7 %) nitric oxide. Five patients (29%) received leukoreduction therapy by the mean of exchange transfusion. The median WBC value was 105 ×109 L–1 (IQR 71–125) prior to leukoreduction. The WBC deceased to a half in all patients after blood exchange [median WBC=46 ×L–1 (IQR 45–60)].
All patients received intra venous erythromycin to reduce their infectivity. Four patients (23%) had bacterial coinfection with bacterial proof in 3 cases (enterobacter cloacae in 1 case, streptococcus pneumoniae in one case and hemophilus influenzea in the last case). Bacterial coinfection occurred in two deaths. The cause of death was related to septic shock in one of them.
Complications occurred in 6 patients: nosocomial infection in 5 patients and femoral venous thrombosis post catheterization in one case.
Four patients (23%) died during the acute hospital course; 2 of these deaths occurred few hours after PICU admission. Time of death ranged from 1 to 30 days after admission. The death was attributed to refractory shock in 3 cases and cerebral death in 1 case. High PRISM (p=0,007), shock (p=0,002), tachycardia (p=0,005), seizures (p=0,006), altered mental status (p=0,006), elevated WBC count (p=0,003) and hemodynamic support (p=0,022) significantly differentiated patients who died from survivors.
RSV is a single-stranded RNA enveloped virus belonging to the recently named Pneumoviridae family, Orthopneumovirus genus, which causes lower respiratory tract illness. Infection does not confer immunity to upper respiratory tract reinfection. The peak of severe disease is among infants in the first 3 months of life. Prematurity, low birth weight, male sex, broncho-pulmonary dysplasia, congenital heart disease, immunodeficiency, cerebral palsy, and Down’s syndrome are risk factors for severe RSV bronchiolitis, but 50–80% of emergency admissions occur in otherwise healthy infants born at term. Worldwide, RSV disease in children under the age of 5 years accounts for an estimated 33.8 million lower respiratory tract infections, 3.4 million hospitalizations, and up to 200,000 deaths annually.
Despite a consensus on the need for an RSV vaccine, there is no licensed product available yet, mainly due to the early age of infection, the capacity of RSV to evade innate immunity, and the failure of RSV-induced adaptive immunity to prevent re-infection. Several clinical trials are now ongoing to assess the safety and effectiveness of different RSV vaccine candidates. Owing to the substantial burden of RSV disease worldwide, RSV vaccine continues to be a necessity for most infants, children and also the elderly. The ideal vaccine should produce long-lasting immunity characterized by a robust Th1-mediated response and high titers of neutralizing antibodies; furthermore, it should protect against both RSV-A and RSV-B, in the presence of maternal antibodies as well, and avoid vaccine-enhanced disease.
Following the first clinical vaccine trial in the 1960s, significant progress has been made. Improved understanding of RSV immunology and structural biology as well as recent advances in vaccine technology are the bases of some of the successes. There are currently a large number of candidates in the pre-clinical phase or undergoing clinical trials, and we are waiting for the information to become available from these studies. Among the candidates in advanced clinical trials, nanoparticle and subunit vaccines are the most promising for pregnant women and the elderly, whereas live-attenuated, vector-based or subunit vaccines are being considered the paediatric population. Ongoing studies could identify effective candidates. An active instrument against infection is needed since RSV infection can cause serious complications in infants, young children and the elderly.
Nasopharyngeal samples were obtained by inserting a swab into both nostrils parallel to the palate (Mini-Tip Culture Direct, Becton-Dickinson Microbiology System, MD 21152, USA) and a second swab from the posterior pharyngeal and tonsillar areas (Viral Culturette, Becton-Dickinson Microbiology Systems, MD, USA). Both nasal and pharyngeal swabs were placed into the same tube containing viral transport medium (minimal essential medium with 2% fetal bovine serum, amphotericin B 20 μg/ml, neomycin 40 μg/ml). Two aliquots of each fresh specimen were stored at − 20 °C to be used for posterior analysis of respiratory viruses and detect atypical pathogens by PCR.
This study has been approved by Ethics Committees of the Universidad Peruana de Ciencias Aplicadas. Parents and caregivers signed a written consent in the previous study which included a section that granted the investigators permission for a possible future use of the samples that could be given as an extension of the original research.
In conclusions, clinical manifestations of pertussis in infants can overlap with several different diseases. Sometimes presentation may mimic a viral respiratory tract infection. Our data support a routinely use of RT-PCR for pertussis in all infants ≤3 months of age with any respiratory symptoms in order to implement appropriate control measures in hospital and in the community at large as the clinical suspicion is often not enough to well recognize pertussis infection.
To the best of our knowledge, this is among the largest prospective multicenter studies regarding the microbiology of acute bronchitis. Notably, about 50% of patients with acute bronchitis and acceptable sputum had evidence of bacterial infection (typical or atypical), a higher frequency than that of viral infection. Also, the distributions of infectious etiologies differed by age and the presence of underlying chronic lung disease. Finally, mixed infections were common, and >50% of patients with viral infections also had bacterial infections.
In recent placebo-controlled randomized trials, antibiotics appeared to provide minimal benefit in treating acute bronchitis [4, 5, 22]. Therefore, it is often assumed that acute bronchitis is primarily a viral disease [4, 5]. Accordingly, previous studies have usually focused on viral etiologies and did not include sputum cultures, or used only serological tests for bacteria, and may have underestimated the bacteria’s role in acute bronchitis [23–25]. Creer et al. detected bacteria and viruses in 26% and 63% of acute bronchitis patients, respectively, prompting the authors to consider bacterial infection relatively uncommon. However, they collected sputum specimens for bacterial cultures from only a portion of patients, most patients submitted swabs and nasal aspirates for viral testing, and sputum specimen adequacy was not discussed. In contrast, we collected sputum specimens from all patients for viral, typical bacterial, and atypical bacterial infection simultaneously.
Although previous studies showed that antibiotics have little benefit in treating acute bronchitis, several factors may have affected the results [4, 5, 27]. First, patients included in such studies were inhomogeneous, and a considerable proportion of them may have had only upper respiratory tract infections (URIs). It is more appropriate to evaluate antibiotic effects in a fully differentiated group of bacterial etiologies. Second, the use of the term ‘bacterial infection’ in the lower respiratory tract does not necessarily imply that there is a requirement for antibiotics. Many of these infections can be cured without antibiotics. Third, even if bacterial infections were treated using antibiotics, subjective symptoms, such as post-infectious cough or upper-airway cough syndrome, might persist. Interestingly, in a randomized controlled trial of patients with URIs, antibiotics were clinically beneficial for a subgroup whose nasopharyngeal secretions contained respiratory bacteria. Although the presence of bacterial agents does not always indicate a disease, antibiotic treatments might be beneficial in subgroups of patients with bacterial etiologies. C-reactive protein or procalcitonin levels may eventually provide an objective marker for evaluating the need for antibiotic treatment.
Recent studies have used the term “lower respiratory tract infection (LRTI)” for conditions approximating acute bronchitis. LRTI is characterized by acute cough, with at least one other lower respiratory tract symptom, including purulent sputum, dyspnea, wheezing, chest discomfort, or chest pain [1, 4, 7, 10]. In our study, we attempted to limit patient enrollment to patients with acute bronchitis; however, some URI patients might have been enrolled because of symptom overlap. This potential bias should be considered when interpreting our results. However, the cohort of 291 patients with acceptable sputum could be considered as a purer group of acute bronchitis patients. Patients with acceptable sputum had more sputum production and auscultatory abnormalities, strongly supporting the diagnosis of LRTI.
In earlier studies, viral prevalence was 9.2–61.3% and rhinovirus or influenza were most commonly detected [7, 8, 26, 32, 33]. Importantly, not all studies spanned an entire year, and some were limited to the winter influenza season [25, 33]. We enrolled patients for an entire year, but fewer were enrolled during the winter, likely because we excluded those with typical symptoms of influenza during the winter (December–February).
In our study, the most common bacterial agent was H. influenzae, followed by S. pneumoniae. Some previous studies found S. pneumoniae to be the most frequent pathogen [7, 26], while others found H. influenzae more frequently [28, 34]. However, with the detection of pneumococcal antigens in sputum or urine, or PCR on airway secretions, S. pneumoniae is found in 17–19% of LRTI cases [7, 26]. Because we only used sputum cultures to detect typical bacteria, the incidence of S. pneumoniae might have been underestimated. Interestingly, S. pneumoniae was isolated in older patients twice as commonly than in younger patients (≥60 vs. <40 years: 15.0% vs. 7.3%, p = 0.075). Therefore, pneumococcal vaccines may be beneficial in preventing acute bronchitis associated with S. pneumoniae in older patients. Additional studies are warranted.
Mixed infection occurred in 18.9% of our patients, in 22–32% of patients in previous studies of LRTI [7, 8, 26], and in 6–26% of non-immunocompromised adults with community-acquired pneumonia (CAP). The most typical combination has been viral-bacterial mixed infection [10, 35]. In our study, rhinovirus was the most common virus in mixed infections. Several studies have suggested that rhinovirus can be pathogenic for LRTI, but it is unclear whether rhinovirus triggers secondary bacterial infection [36–38]. Also, viral-bacterial mixed infections have induced more severe inflammation and disease than individual infections in CAP cases [35, 39, 40]. Clinical features and outcomes have not been studied in patients with mixed infection acute bronchitis or LRTI without pneumonia, and we found no distinct characteristics of mixed infections.
We did not exclude patients with chronic lung disease, a large proportion of the patients evaluated for cough in our clinics. In a recent review, Mohan et al. detected viruses via PCR and RT-PCR in 34.1% of patients with an acute exacerbation of COPD. The same rate (34.1%) was observed for COPD patients in our study. However, none of our COPD or asthma patients were positive for M. pneumoniae, C. pneumoniae, or B. pertussis. Despite potential methodological problems, studies using PCR also found no COPD exacerbations associated with M. pneumoniae or C. pneumoniae [42, 43]. In a previous multicenter study, we demonstrated the absence of B. pertussis in patients with chronic lung disease.
We found that the prevalences of rhinovirus, adenovirus, and M. pneumoniae with acute bronchitis were higher in young adults. This observation is consistent with prior LRTI studies. Conversely, the frequency of typical bacteria was higher in the older age group, as demonstrated in studies of CAP [45, 46]. This result suggests antibiotics may be more beneficial in older patients with acute bronchitis. Petersen et al. reported that antibiotics substantially reduced pneumonia risk after chest infection (acute bronchitis), particularly in elderly patients.
In summary, bacterial infections were identified as the etiology for about half of the 35.9% of acute bronchitis patients who had acceptable sputum. The infectious etiologies differed by age and the presence of underlying chronic lung disease. Further, mixed infection with both bacteria and viruses were common. Future research should be directed at the identification of patient groups most likely to benefit from antibiotic treatment.
This study was approved by the institutional review boards (IRB) of Seoul St. Mary's Hospital (IRB approval number: XC09TIM-I0081K) and of other 2 hospitals. All parents and guardians provided an informed consent before enrolling the patients.
Nasopharyngeal swab specimens were collected from enrolled patients, placed in a tube with viral transport media, and maintained under refrigeration until they were sent to the Molecular Biology Laboratory of the Infectious Diseases Department, Instituto Nacional de Ciencias Médicas Salvador Zubirán, where they were stored at −70°C. Samples from the patients enrolled in San Luis Potosí were maintained under refrigeration and transported to the Medical School (Universidad Autónoma de San Luis Potosí) where they were stored at −70°C until they were sent to the Instituto Nacional de Ciencias Médicas Salvador Zubirán for storage and virological testing; the samples sent from San Luis Potosí to Mexico City were shipped on dry ice.
All nasopharyngeal swabs were tested by real‐time polymerase chain reaction (RT‐PCR) for influenza A following the Centers for Disease Control and Prevention protocol as described previously.12 Respiratory samples were also tested with the RespiFinder 19 (April 2010 to May 2012) or RespiFinder 22 (previously RespiFinder Plus, June 2012 to March 2014), from PathoFinder BV, Maastricht, the Netherlands. This multiplex RT‐PCR test can detect and differentiate 15 viruses (coronavirus NL63, OC43, and 229E, human metapneumovirus, influenza A, influenza AH5N1, influenza B, parainfluenza virus types 1 to 4, RSV A and B, rhinovirus, and adenovirus), as well as four bacteria (Bordetella pertussis, Chlamydophila pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae). RespiFinder 22 removed influenza H5N1 and added bocavirus (type 1), coronavirus HKU1, influenza A H1N1v, and enterovirus.
The FilmArray RP v1.7 targets 19 organisms, including ADV, influenza A viruses H1, 2009H1, H3 (FluA-H1, FluA-2009H1, FluA-H3) and FluB, parainfluenza virus types 1 to 4 (Para 1–4), coronaviruses 229E, HKU1, OC43, and NL63 (Cov-HKU1, NL63, 229E, OC43), human metapneumovirus (hMPV), RSV, human rhinovirus/enterovirus (Rhino/Entero), C. pneumoniae, M. pneumoniae and B. pertussis. The FilmArray RP assay was performed according to the manufacturer’s instructions. The principle of the assay has been previously described [8, 12]. Each pouch included internal run controls for every step, and results for the assay were only provided by the software if the quality control reactions showed appropriate results.