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Of the 349 children included in the study, 178 were RSV positive. The majority of
children (56% or 100 children) with diagnoses of RSV were afebrile. Febrile children
who were RSV positive were more than twice as likely to be diagnosed with bacterial
pneumonia as those who were afebrile (47/78 or 60% vs 27/100 or 27%,
P < .001). In the 171 children who had RSV-negative
bronchiolitis (diagnosis of viral infection other than RSV), 88/171 (or 51%) were
afebrile. Febrile children with RSV-negative bronchiolitis were 8 times more likely
to be diagnosed with pneumonia as afebrile children (54/83 or 65% vs 7/88 or 8%,
P < .001).
Additional bivariate and trivariate analyses of both RSV-positive and RSV-negative
bronchiolitis did not show any significant difference between the occurrence of
pneumonia in children with fevers in the 100.4°F to 100.9°F range versus fevers in
the >102°F range.
The primary study subjects were 5,298 patients, who underwent multiplex real-time polymerase chain reaction (PCR) for simultaneous detection of respiratory viruses, among who visited the emergency department or outpatient clinic with respiratory symptoms at Ulsan University Hospital from April 2013 to March 2016 (Figure 1). The medical records of all these patients were retrospectively reviewed in detail.
Respiratory viral infection is a significant etiology for community-acquired pneumonia123. With the development of detection techniques, respiratory viruses have been detected in 10%–30% patients with community-acquired pneumonia45. Respiratory virus infections are also a frequent cause of bacterial pneumonia. In a systematic review of previous studies, the proportion of bacterial pneumonia in patients with influenza was found to range between 11% and 35%6.
In a study of pandemic and seasonal influenza virus infections, the most common bacterial pathogens found in patients with post-influenza pneumonia were Staphylococcus aureus and Streptococcus pneumoniae78. Elucidation of the pneumonia-causing pathogens in patients with respiratory viral infection is important, because respiratory viral infection complicating bacterial pneumonia is associated with a worse prognosis and high mortality rate compared with respiratory viral infection only 9, although the prognosis can be improved with early and appropriate empirical antibiotic treatment7910. However, the predominant bacterial species causing pneumonia secondary to respiratory viral infections other than influenza remain unknown. Accordingly, the aim of the present study was to know whether the pathogens causing post-viral bacterial pneumonia vary according to the type of preceding respiratory virus.
This research was submitted to our university institutional review board and was
approved. The IRBNet ID is 1083099-2.
Among HAdV pneumonias, severe pneumonia was observed in five patients. Severe pneumonia patients and others did not differ significantly with respect to demographic characteristics and most symptoms (S3 Table). However, high fever, dyspnea, and chest discomfort were more frequent and febrile periods were significantly longer among patients with severe HAdV pneumonia, compared to others (8.6 ± 1.9 vs. 6.3 ± 1.6 days; p = 0.002). The time from fever onset to the greatest radiologic aggravation (increased opacity on follow-up chest X-ray) was also longer in the severe group (9.0 ± 2.7 vs. 6.3 ± 1.6, p = 0.001). Severe HAdV pneumonia was associated with a lower white blood cell count (WBC) and platelet count on admission day (p <0.001 and p = 0.042, respectively). Although the mean CRP value was higher in the severe group (p = 0.002), the mean serum procalcitonin concentration did not differ significantly between patients with severe pneumonia and others (p = 0.102; S4 Table).
Pneumonia: If a child presents with severe malnutrition with any sign of pneumonia (any of the WHO defined signs of pneumonia or severe pneumonia or radiological pneumonia) would be considered as pneumonia.
A child with severe malnutrition with cough or respiratory difficulty with the presence of end point consolidation or other infiltrates, or pleural effusion in chest X-ray defined by WHO, as assessed by a qualified radiologist.
Clinical characteristics of pneumonia: According to WHO, a child with a history of cough with respiratory difficulty or age-specific fast breathing or lower chest wall indrawing will be defined as pneumonia.
According to WHO, a child with a history of cough and/or respiratory difficulty plus oxygen saturation < 90% or central cyanosis, or severe respiratory distress (grunting, very severe chest in-drawing), or signs of pneumonia with a general danger sign (inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions), auscultatory findings of decreased or bronchial breath sounds or signs of pleural effusion or empyema will be defined as severe pneumonia.
There were some complications among HAdV pneumonia patients. Acute heart failure occurred in two patients. Delirium occurred in one patient. One patient developed upper-extremity deep vein thrombosis, possibly resulting from a central line catheter. Two patients required mechanical ventilation. Of these latter patients, one expired from respiratory and heart failure (Table 4).
Adenovirus is a well-known pathogen of mild upper respiratory tract illness which is usually self-limited. In pediatric patients, adenovirus pneumonia can present with the features of bacterial pneumonia (1). Many cases of fatal adenovirus respiratory infection in immune-suppressed adults have been described in the literature. Because humoral and cellular immunity are generally important in overcoming viral infection, life-threatening adenovirus pneumonia in patients with defective or deficient T-cell immunity, such as those with bone marrow or solid organ transplant, malignant neoplasm, or AIDS, has been reported (2345). However, there have been a few cases of adenovirus pneumonia in immunocompetent adults. Historically, epidemics and outbreaks of adenovirus pneumonia in military recruits and health care facilities have been described (6789). These cases have raised concerns about adenovirus infection in the general population, but there is still limited information on the condition.
We had encountered several patients in our clinical practice with adenovirus pneumonia that rapidly progressed to respiratory failure, and we thought that it was worthwhile to report the clinical and radiological spectra of adenovirus pneumonia in civilian adults. Furthermore, if any clinico-radiological factors appeared to foreshadow the development of acute respiratory distress syndrome (ARDS), aggressive treatment and careful follow-up evaluation can be prepared in advance. Thus, the aim of our study was to identify the incidence, clinical features, survival outcome, and radiological findings of adenovirus pneumonia acquired in the community. We also compared clinico-radiological factors between patients with and without ARDS in order to determine possible predictors for patients who might develop respiratory failure.
A 44-year-old Caucasian woman was admitted to our emergency department with a three-day history of a febrile illness associated with sore throat, dry cough, myalgia and diarrhea. One day prior to admission she had developed a widespread, non-pruritic, erythematous rash. Her medical history consisted of hypertension, for which she was taking atenolol, and several episodes of gout, for which she was taking allopurinol.
Her physical examination revealed that she was obese, had a body temperature of 39.0°C, a pulse rate of 112beats/minute and blood pressure of 145/90 mmHg. Her respiratory rate was 20 breaths/minute with oxygen saturation of 94% on room air. Her chest auscultation was unremarkable. She had a widespread, erythematous maculopapular rash with scattered petechiae on both legs. Examination of the oropharynx revealed erythema but no exudate.
Initial laboratory tests showed a white cell count of 9.2 × 109/L, a neutrophil count of 7.9 × 109/L, a lymphocyte count of 0.69 × 109/L, a platelet count of 254 × 109/L, a C-reactive protein concentration of 169 mg/L, an alanine aminotransferase level of 22 IU/mL, a creatinine phosphokinase (CPK) level of 950 IU/mL and a creatinine concentration of 73 μmol/L. Her HIV test was negative. Her anti-nuclear antibodies, rheumatoid factor and anti-neutrophil cytoplasmic antibodies were negative, and her complement components C3 and C4 and immunoglobulin levels were within the normal range. Her initial chest radiograph was unremarkable. She was commenced on intravenous ceftriaxone for presumed meningococcal disease.
Twenty-four hours following admission her condition rapidly deteriorated with acute respiratory failure and hypotension requiring admission to the intensive care unit for mechanical ventilation and vasopressor support. A repeat chest radiograph showed widespread interstitial infiltrates bilaterally (Figure 1). Her antibiotics were changed to imipenem and doxycycline to treat presumed bacterial pneumonia, and oseltamivir was empirically added to treat a possible 2009 pandemic influenza A (H1N1) infection.
Bacterial cultures of her blood and sputum, Legionella antigen testing of her urine, and a polymerase chain reaction (PCR) assay of her blood for Neisseria meningitidis and Streptococcus pneumoniae were all negative. Her nasopharyngeal and tracheal samples were negative for influenza A and B (including H1N1), respiratory syncytial virus (RSV) types A and B and parainfluenza virus (PIV) types 1 through 4, but they were positive for adenovirus DNA on the basis of PCR assay (using the hexon gene as the target for amplification), with a cycle threshold value of 18. Subsequent sequencing analysis performed at the respiratory Virus Reference Laboratory, London, revealed the isolate to belong to serotype 4.
The patient made an uncomplicated recovery without any specific antiviral therapy and was extubated on the fifth day of her admission. Antibiotics were stopped after a total of five days, and she was discharged to home on the ninth day of her admission. Further tests for immunodeficiency were negative.
We performed a literature search of MEDLINE for cases of community-acquired adenovirus pneumonia in immunocompetent adults. We used the search terms "adenovirus," "pneumonia," "immunocompetent," "adult" and "civilian." We excluded cases that involved military recruits, nosocomial cases and those cases in which bacterial pathogens were also implicated.
We identified 19 articles published between 1975 and 2008 describing 21 patients that matched our search terms. The demographic, laboratory, radiological and clinical details of these cases and our own are shown in Table 1.
Of the 21 cases retrieved in our literature search, 57% of the patients were men, and overall the patients' median age was 40 years (age range, 18 to 60 years). Where recorded, the commonest ethnic origin of patients was Caucasian (40%). Significant co-morbidity was uncommon among patients, but obesity was frequently noted as an examination finding.
The median duration of illness prior to admission to the hospital was five days. The following presenting symptoms were noted: fever (90%), cough (81%), dyspnea (70%), myalgia (57%), sore throat (29%), abdominal pain (14%) and diarrhea (10%). Common examination findings on presentation included abnormalities in chest auscultation (90%), pyrexia (89%) and hypoxia (66%). The presence of pharyngitis, conjunctivitis or rash was noted infrequently (19%, 19% and 5% respectively).
The median white cell count on admission to the hospital was 7.7 × 109 (range, 3.9 × 109 to 28 × 109), although neutrophilia was relatively common (33%). Lymphopenia and thrombocytopenia were noted in 52% and 19% of patients, respectively. Other frequently noted laboratory abnormalities were mildly elevated transaminases and elevated levels of CPK.
The chest radiograph at presentation was abnormal in 90% of patients. The most common pattern of abnormality was bilateral interstitial infiltrates (57%), although lobar consolidation was also noted reasonably frequently (24%).
Intubation and mechanical ventilation were required in 67% of patients and occurred at a median of one and half days following admission. Overall 24% of patients died. The median length of stay in the hospital was 21 days. Two patients received antiviral therapy with cidofovir, one of whom died.
Where recorded, the most common adenovirus serotypes identified were serotype 7 (24%), serotype 3 (19%), serotype 21 (14%) and serotype 4 (10%). The diagnosis was made most frequently on the basis of lower respiratory tract samples (principally bronchoscopic alveolar lavage fluid and lung biopsy tissue), and viral culture was the most common method of adenovirus detection (76%). There were no cases identified in the literature where molecular methods were used to diagnose adenovirus pneumonia.
Escherichia coli accounts for 4% of cases of CAP and 5–20% of cases of HAP or HCAP. It occurs most commonly in debilitated patients. The typical history is one of abrupt onset of fever, chills, dyspnea, pleuritic pain, and productive cough in a patient with preexisting chronic disease.
The radiographic manifestations usually are those of bronchopneumonia; rarely a pattern of lobar pneumonia may be seen.
Viral pneumonia and lower respiratory tract infections are increasingly being recognized in adult patients including the critically ill.1,2 It appears that most viral lower respiratory tract infections are community-acquired and account for a significant etiology in mechanically ventilated patients with severe community-acquired pneumonia.3,4 Bacterial-viral co-infections are best described with influenza. The long history of bacterial infections occurring concurrently or shortly after influenza illness dates back to the 1918 influenza pandemic in which most of the fatal cases were found to be due to co-infection based on autopsy findings.5 More recently the 2009 H1N1 influenza pandemic was complicated by bacterial pneumonia in 4% to 33% of hospitalized or critically ill patients.6–11 Most commonly isolated co-infecting bacterial organisms with influenza are Streptococcus pneumoniae, Staphylococcus aureus, S. pyogenes, and Haemophilus influenzae. Influenza seasons are not equal as some are associated with lower mortality potentially related to differences in virulence factors or other unknown reasons.12–15
Bacterial co-infection is not limited to influenza and has been described with numerous other respiratory viruses, including respiratory syncytial virus (RSV), parainfluenza virus (PIV), rhinovirus, adenovirus, and human metapneumovirus (hMPV).16–25Advanced technologies have allowed for increased recognition of viral pathogens and diagnoses of viral respiratory infections including pneumonia.26 Several mechanisms by which viral respiratory infections may predispose patients to bacterial co-infections have been investigated including virus-induced alterations in epithelial cells, impaired immune response, and enhanced bacterial colonization.27 Utilizing new diagnostic technologies, it may be possible to better describe the clinical aspects of viral pneumonia and interactions with other infecting organisms. The purpose of this study was to describe hospitalized adult patients with viral pneumonia including possible co-infections and clinical outcomes.
Klebsiella pneumoniae is among the most common gram-negative bacteria accounting for 0.5–5.0% of all cases of pneumonia. These features are bulging fissures, sharp margins of the advancing border of the pneumonic infiltrate and early abscess formation. CT findings consist of ground-glass attenuation, consolidation, and intralobular reticular opacity, often associated with pleural effusion. Complications of Klebsiella pneumonia include abscess formation, parapneumonic effusion, and empyema.
A clinical outcome was available for 357 of the 382 study episodes. Of the 357 study episodes with clinical outcome available, in 108, the patient stayed in the hospital for more than 13 nights, in 127, the patient had a revisit and in 29, the patient died during the hospital stay (Table 5).
In study episodes diagnosed with pneumonia, the presence of a respiratory virus was neither associated with clinical outcomes (i.e. over 13-night hospital stay, number of revisits or death at ward) nor with WBC values over 15 × 109/L or CRP values over 100 mg/l (all P > .1, Table 4). Similar results were also seen with lower WBC and CRP cutoff values of 10 × 109/L and 80 mg/l, respectively (data not shown). Also in connection with study episodes diagnosed with pneumonia, there was no association between the above mentioned clinical outcomes and laboratory findings (WBC over 15 × 109/L/l or CRP over 100 mg/l) (P > .2). In study episodes diagnosed with pneumonia and with dyspnea, death at ward was seen in 15% of the study episodes, whereas in connection to study episodes diagnosed with pneumonia but without dyspnea, the same was true in 5.3% of the study episodes, although this difference was not statistically significant (P = 0.07). However, study episodes diagnosed with pneumonia and with dyspnea lasted longer than study episodes diagnosed with pneumonia but without dyspnea (P = .02).
No difference in the number of deaths at ward was seen between study episodes diagnosed with pneumonia and study episodes not diagnosed with pneumonia. A negative association was found between hospital revisit and virus detection; a revisit was less probable when a virus was present than when a virus was not present; 43 (31%) revisits occurred among the virus-positive study episodes and 93 (39%) revisits among the virus-negative study episodes (P < .05, Table 6). Finally, a CRP value over 100 mg/l was associated with death at ward; 21 of the 29 (72%) deceased patients had CRP values over 100 mg/l (P = .04. Table 6).
Our case report and review of the literature provides the first comprehensive review of community-acquired adenovirus pneumonia in immunocompetent adult civilians. Hakim and Tleyjeh published a case report and literature review of adenovirus pneumonia in immunocompetent adults in 2008; however, their cohort was a mix of civilians, military recruits and healthcare-associated cases.
The 21 cases we identified in the literature demonstrate that patients with adenovirus pneumonia usually present with several days' history of a non-specific febrile respiratory illness. These patients frequently have respiratory compromise with hypoxia at the time of presentation, while the classical features of adenoviral infection, such as pharyngitis, conjunctivitis, rash or diarrhea, are usually absent. The clinical condition of most patients deteriorates rapidly during admission and requires intubation and ventilation, a pattern commonly seen with primary influenza pneumonia. Laboratory findings are also typical of viral infection, with a normal total white cell count, relative lymphopenia, thrombocytopenia and elevated transaminases and CPK being frequently observed. The most commonly seen radiological pattern on admission is widespread bilateral interstitial shadowing, which is consistent with the results reported in a case series describing the radiological appearance of adult patients with confirmed adenoviral pneumonia. It is noteworthy that several patients, including our own case, had normal initial chest radiography results. Lobar consolidation, a pattern considered more suggestive of bacterial infection, was observed in around one-fourth of patients with adenoviral pneumonia. All of these radiological patterns (including normal initial chest radiographs) have been described in patients with primary influenza pneumonia. Although the overall mortality rate in this series was 24%, only two patients who were reported on after 1979 have died, possibly representing improvement in supportive care over this time period.
Our present case report of an immunocompetent adult civilian patient with sporadic adenoviral pneumonia is the first case to be reported in the literature in which molecular diagnostic methods were used. Nucleic acid detection has the advantages of increased sensitivity and rapid availability of results compared to the conventional diagnostic techniques of viral culture and antigen detection. In addition, multiplex real-time reverse transcriptase PCR (RT-PCR) assays are increasingly being used by diagnostic laboratories to detect a wide range of respiratory viruses in a single reaction. While it is well-recognized that influenza virus and adenovirus can cause pneumonia, there is increasing evidence that other respiratory viruses, such as RSV, human metapneumovirus, PIV, human rhinovirus and human coronavirus play an important role in the etiology of community-acquired pneumonia in adults. The increasingly widespread use of multiplex real-time RT-PCR for the detection of respiratory viruses in clinical practice will allow us to accurately determine the burden of respiratory viral infection in patients with community-acquired pneumonia and may demonstrate that adenoviral pneumonia in immunocompetent adults is more common than previously thought.
The advantages of rapidly diagnosing respiratory viral infection in patients with community-acquired pneumonia include the institution of appropriate infection control measures, the rational use of antibiotics in the absence of bacterial co-pathogens and, in some instances, the use of specific antiviral therapy. Two patients in our series received the antiviral agent cidofovir, and while there are no randomized, controlled trials demonstrating its efficacy in adenoviral infection, it has been used successfully in immunocompromised patients with severe adenoviral pneumonia.
In China, pneumonia ranks fifth among all causes of death in humans. However, there are limited data regarding the etiology of community-acquired pneumonia (CAP) worldwide and in China, with about 17% to 48% unknown. This may lead to inappropriate antimicrobial therapy and emergence of drug-resistant bacteria.
Since influenza virus was first isolated in ferrets from pneumonia patients in 1933 by Smith, viral etiology of pneumonia has attracted more and more attention. Recently, our ability to detect viral pathogens has dramatically improved after the introduction of highly sensitive nucleic amplification tests (NATs). Additionally, NATs has its superiority in detection of viruses that are difficult to grow in cell culture, such as human rhinovirus (HRV), human coronaviruses (HCoV), and new emerging pathogens human metapneumovirus (hMPV) and human bocavirus (HBoV).
Recently epidemiological surveys on etiology of CAP showed that respiratory viruses accounted for 15% to 56% of cases. However, the real role of virus in pneumonia was few studied and still controversial. It may partially due to poor sensitivity of most viral testing assays (except NATs). However, it was difficult to confirm the pathogenicity of virus tested by NATs. Thus, clinical features of specific viral pneumonia were not well described. After combined the improvement in sensitivity and specificity of viral testing assay with more comprehensive design study, more valuable information will be available.
Moreover, because there is limited information concerning to the prevalence and clinical features of viral pneumonia, guideline of diagnosis and treatment of CAP does not provide much recommendation about the assessment and management of viral CAP.
In order to better understand the real role of respiratory virus in pneumonia and better manage the patients, we conducted a prospective observational study to reveal the viral etiology of adult CAP in Guangzhou, as compared with etiology of patients diagnosed with influenza like illness (ILI) and with volunteer controls.
We identified 19 adult patients (14 males and 5 females; median age, 38 years) who were diagnosed with adenovirus pneumonia between March 2003 and April 2015 in a single tertiary-referral hospital. All patients underwent Gram stains, bacterial and fungal cultures of blood and urine. Sputum was stained and cultured for bacteria, mycobacteria, and fungi. Specimens from patients who underwent bronchoscopy with the collection of bronchoalveolar lavage (BAL) fluid or lung biopsy, as well as those who underwent surgical biopsy, were stained and cultured for bacteria, mycobacteria, and fungi. In addition, polymerase chain reaction (PCR) analysis for BAL specimens and nasal or throat swabs were performed to detect viral organisms. Patients in whom other infectious organisms were identified in the sputum, blood, urine, nasal and throat swabs, BAL fluid, or lung specimen within four weeks of adenovirus identification were regarded to have a concurrent infection and were excluded from this study. Finally, 19 patients confirmed to have only adenovirus pneumonia were included in this study; these patients included the five patients whose imaging features were published in our previous study (10).
All data including age, sex, premorbid conditions, symptoms, laboratory and pathological findings, clinical course, treatment, and survival outcome were drawn from patient electronic medical records. Patients were regarded as having ARDS when they satisfied the American-European Consensus Conference definition for the condition: acute onset of respiratory failure, bilateral infiltrates on chest radiograph, hypoxemia as defined by a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2 ratio) ≤ 200 mm Hg, and no evidence of left atrial hypertension or pulmonary capillary pressure < 18 mm Hg (if measured) to rule out cardiogenic edema (11).
The mean WBC value was 13.8 × 109/L in study episodes with pneumonia and 11.1 × 109/L in study episodes without pneumonia, but this difference was not statistically significant (P = 0.07, Table 3). As a categorical variable, WBC over 15 × 109/L was associated with study episodes diagnosed with pneumonia (P < .006, Table 3).
The mean CRP value was 146 mg/l in study episodes with pneumonia and 105 mg/l in study episodes without pneumonia (P < 0.001). As a categorical variable, a CRP value over 100 mg/l, or even over 80 mg/l, was associated with a pneumonia finding in the chest radiograph (P < .05 for both, Table 3).
When comparing study episodes diagnosed with pneumonia and with one or more respiratory viruses, and study episodes diagnosed with pneumonia but without respiratory viruses, no differences between WBC or CRP values were found (P > .2, Table 4). Corresponding effects of the most common viruses (rhinovirus, influenza virus, coronavirus, RSV and parainfluenza virus) were also tested separately, and no differences were found (P > .1).
Interactions between viral and bacterial respiratory pathogens have been recognized dating back to the 1918 influenza pandemic. Bacterial pneumonia is a well-recognized serious complication of influenza infections and coinfections are commonplace [2–10]. Respiratory syncytial virus (RSV), parainfluenza viruses, rhinoviruses, and adenoviruses have also been linked to bacterial coinfections in humans [11–18]. Animal studies have suggested synergism between bacterial pathogens and other respiratory viruses [19, 20]. The relationship between viral and bacterial respiratory infections creates a difficult situation for clinicians determining the appropriate use of antimicrobials as they treat hospitalized patients with pneumonia while also trying to minimize the development and selection of resistant organisms.
Respiratory viruses are increasingly recognized as the primary etiology of pneumonia among patients requiring hospitalization (2.7–5 % of pneumonia cases) [21, 22]. Advanced technologies using multiplex molecular assays and PCR improve the diagnostic ability to identify viral pathogens in a timely manner and may impact the use of antibacterials in patients with no bacterial infection identified.
Several studies have investigated the impact of respiratory viral pathogen identification on antibacterial exposure [23–26]. Decreased antibiotic use was observed in two pediatric studies assessing the impact of rapid viral diagnostic tests for respiratory tract infections; however, these results were not mirrored in similar adult studies [23–25]. These studies all used immunofluorescent staining as the primary diagnostic technology. To our knowledge, only one study using PCR-based respiratory virus detection has been reported and found no change in antibacterial use with improved diagnoses for lower respiratory tract infections.
Broad-spectrum antibacterial exposure increases the risk of subsequent infections with multidrug-resistant organisms (MDROs) and leads to a vicious cycle of empiric broad-spectrum antibacterials to combat increasingly resistant organisms. We and others have previously shown that patients with culture-negative pneumonia frequently receive treatment with broad-spectrum antibiotics, usually in excess of 5–6 days of therapy despite lack of evidence for a bacterial etiology of infection [28, 29]. It is important to recognize that these studies were performed prior to the availability of rapid viral diagnostics which may have influenced how antibiotics were used during those study periods. Use of new diagnostic technologies for respiratory virus detection could decrease unnecessary antibacterial exposures and subsequent MDRO infections. This study aimed to describe the use of continued empiric antibacterials in patients with known viral pneumonia and to determine the impact of such therapies on subsequent bacterial infections/colonization and clinical outcomes.
Globally, pneumonia is the leading cause of hospitalizations and death among children with nearly 120 million new cases and one million deaths each year. In Australia, pneumonia is associated with 5–8 hospitalisations per 1000 child-years among children < 5 years old, with deaths being rare. Australian Aboriginal children are 14 times more at risk of infectious diseases than non-Aboriginal children.
Respiratory bacteria and viruses are frequently detected in specimens collected from children with pneumonia. Identifying the infectious agents associated with illness can guide management of the infection and facilitate judicious use of antibiotics. Differentiating bacterial from viral pneumonia based on clinical characteristics is challenging as the clinical signs and symptoms overlap [5, 6].
Despite the growing availability of molecular techniques for pathogen detection, including quantitative and qualitative pathogen detection, laboratory results are usually only available after treatment decisions have been made. Several studies have assessed the utility of non-specific inflammatory biomarkers such as C-reactive protein (CRP), an acute-phase reactant released in response to cytokine interleukin-6, white cell count (WCC) and absolute neutrophil count (ANC) to discriminate probable bacterial infections from non-bacterial infections and also to assess the severity of illness [7, 8]. Bacterial pneumonia has been associated with higher CRP, WCC and ANC than viral pneumonia [8–11], while some studies have found no difference in biomarkers among bacterial and viral cases of pneumonia [12, 13]. Even studies that report differences in these biomarkers cannot determine any reliable thresholds for differentiating bacterial pneumonia from viral pneumonia [10, 14]. Previous studies were also affected by small sample size, use of less sensitive methods for pathogen detection which could have resulted an inaccurate categorization of bacterial and viral cases [12, 14]. Furthermore, studies have been conducted in low-income settings where the contribution of bacterial infection may be higher and where children are at higher risk of other infectious diseases that could influence the biomarker levels and confound the analysis.
The aetiology of childhood pneumonia has changed in high-income settings with routine pneumococcal conjugate vaccination program – decrease in bacterial aetiology and increase in viral aetiology have been reported [15, 16]. However, the utility of inflammatory biomarkers in a highly-vaccinated paediatric population with pneumonia to differentiate bacterial from viral pneumonia has rarely been assessed. We therefore assessed the distribution of inflammatory biomarkers (CRP, WCC and ANC) in blood samples from a prospective case-control study of Western Australian children with radiologically-confirmed pneumonia. We compared the clinical characteristics and biomarkers level among pneumonia cases detected with bacteria and viruses. We assessed the cut-off threshold of these biomarkers for discriminating bacterial pneumonia from viral pneumonia. Findings from this study could help in developing a rapid point-of-care diagnostic tool or algorithm to predict the likely causative pathogen and to assist clinicians to target management of childhood pneumonia.
In order to test the different between mild and severe HAdV pneumonia cases, comparison of clinical manifestations was undertaken. As shown in Table 3, successful HAdV typing was performed in 174 cases, the results showed no significant differences in clinical manifestations such as cough, wheezing, vomiting, and skin rashes between the mild pneumonia cases and severe pneumonia cases. However, in the severe pneumonia children, severe disease performances such as the shortness of breath, cyanosis, labored breathing, listless, antifeedant, and breathing machine support were noted. The incidence of diarrhea in children with severe pneumonia was higher than that in mild pneumonia children. Besides, compared with mild pneumonia children, children with severe pneumonia showed younger age, longer fever time, higher incidence of fever, and longer hospital stay. No significant difference was observed between the two groups in the percentage of white blood cells and neutrophils, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).
As illustrated in Table 4, the clinical symptoms of mild pneumonia and severe pneumonia in 70 cases of single HAdV infection were found to be similar to the clinical symptoms of mild pneumonia and severe pneumonia in 174 cases of HAdV infection. That is to say, whether it is a single or mixed HAdV infection, severe adenovirus pneumonia is characterized by a small onset age, longer duration of fever, longer hospitalization, and prone to diarrhea. However, among HAdV single infection, children with severe pneumonia were more likely to have wheezing symptoms. According to adenovirus serotype, the 174 patients were divided into 5 groups. Among the children with severe pneumonia, HAdV-7 was more common, followed by HAdV-3. HAdV-1 and HAdV-2 were mostly found in children with light pneumonia. The average viral load of different serotypes were HAdV-1: 2.45 ± 1.89, HAdV-2: 2.66 ± 1.47, HAdV-3: 3.38 ± 2.17, HAdV-7: 3.78 ± 2.28, other types: 2.39 ± 1.55 (log10 copies/μL), and the difference was statistically significant (K-W test, P = 0.015). Pairwise comparison showed that the average viral load of HAdV-7 was higher than that of other types except the HAdV-3, and the difference was statistically significant. No significant difference was noted in other pairwise comparison.
We conducted a case-control study in which we prospectively screened all severely malnourished children aged <5 years admitted to the Dhaka Hospital of International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b) from April 2015 to December 2017. The Dhaka hospital of icddr,b provides care and treatment for approximately 140,000 patients annually mostly from low-socioeconomic urban or peri-urban communities in Dhaka. Sixty percent of patients are aged <5 years admitted with diarrhea only or with diarrhea and other co-morbidities. According to data from Dhaka hospital of icddr,b during 2017, among 6,035 children <5 years with diarrhoea and other co-morbidities around 23% (1,408) were severely malnourished, 24% (1,453) children had pneumonia and 6% (354) had both SAM and pneumonia.
During April 2015 to March 2017, we enrolled children as cases if they were aged <5 years (0–59 months), severely malnourished (i.e., WHO criteria <-3 z score from the median of weight for height/length, weight for age, or nutritional edema) and met WHO clinical criteria for pneumonia. We also enrolled children as cases if they had SAM, cough, and radiological pneumonia. During February 2016 to December 2017, we enrolled SAM children with no pneumonia on admission as controls if they did not have any additional respiratory symptoms and/or signs of pneumonia as classified by the WHO within the past 10 days prior to admission. The only match that was done for our case and control was severe malnutrition and it was done at recruitment. The information was taken from the parents/caregivers. Children who might have chance of migration to outside Dhaka city within a one-month period from admission were not enrolled in the study as we followed-up with enrolled participants during that period to evaluate the death outcome of children with pneumonia related to different viral etiology. Information on chance of migration was validated from the statement of parents/ caregivers.
Community-acquired pneumonia is a leading cause of mortality worldwide. Its diagnosis and treatment have traditionally focused on bacterial pathogens. Recently, nucleic acid amplification testing using polymerase chain reaction (PCR) platforms has greatly improved the diagnosis of respiratory viral infections. Thus, it is now recognized that the rate of viral infection is as high as 27% (1).
Common radiologic patterns of viral pneumonia include patchy bilateral ground-glass opacities (GGOs) and consolidation, which may become confluent. These patterns are not specific for viral pneumonia but overlap with interstitial lung diseases (ILDs) [e.g., cryptogenic organizing pneumonia (COP), acute fibrinous and organizing pneumonia (AFOP), and acute interstitial pneumonia (AIP)]. Patients with the above ILDs complain of progressive dyspnea, which is commonly accompanied by cough and fever, and occasionally by flu-like symptoms, which also overlap with the symptoms of viral pneumonia. Thus, we considered that patients with viral pneumonia may be misdiagnosed with certain ILDs whenever a virus survey is not performed.
The objectives of the present study were to clarify how many patients with viral pneumonia were misdiagnosed with other diseases (including ILDs) and to determine which ILDs were frequently misdiagnosed based on a PCR to detect viruses in bronchoalveolar lavage fluid (BALF).
Between April and December, 2009, consecutive adult patients admitted to the First Affiliated Hospital of Guangzhou Medical University and diagnosed with CAP within 14 days from onset were studied. They were sampled for throat swabs at enrollment and paired sera by at least two weeks interval. CAP was defined as the presence of a new infiltrate on the chest radiographs, together with a new cough or sputum or change in respiratory symptoms, or fever, or sign of consolidation of lung or rales, or leukocytosis (>10 × 109/L) or leucopenia (<4 × 109/L). No alternative diagnosis was responsible to the new infiltrate during follow-up. Exclusion criteria was: 1) immunosuppression (e.g. human immunodeficiency virus infection); 2) previous organ transplantation; 3) immunosuppressive therapy, defined as daily doses 20 mg prednisolone or equivalent for 2 weeks; 4) any dose of an immunosuppressive combination regimen, including azathioprine, cyclosporin and/or cyclophosphamide; 5) treating cancer; 6) lung abscess, aspiration pneumonia and tuberculosis. Pregnant women, patients who were released from hospital within 14 days and who didn’t signature the consent were excluded.
Additionally, ILI patients were enrolled. It was defined as an acute illness within 14 days, with fever (≥38°C), two constitutional symptoms (chills, headache, myalgia or fatigue) and one respiratory symptom (cough, sore throat or coryza), without evidence of pneumonia. Throat swab samples were taken at enrollment and paired sera were taken by two weeks interval.
Both pneumonia patients and ILI patients were followed up via telephone or interview for up to 30 days. All data were recorded by a trained doctor, who was blinded to the results of viral detection.
Moreover, volunteer controls without clues of acute illnesses within one month were also enrolled and sampled for throat swabs.
The study was approved by the ethics committee of The First Affiliated Hospital of Guangzhou Medical University and informed consent was obtained for all subjects.
A total of 230 children with radiologically confirmed community-acquired pneumonia (cases) were enrolled during the study period. Of these, 120 (52%) were male and 147 (64%) aged ≤ 5 years; the median age was 38 months (IQR: 19, 81). Twenty-one (9%) cases were Aboriginal. Of the 230 cases, 210 (91%) had received at least 2 doses of the 13-valent pneumococcal conjugate vaccine. Demographics and existing or ever diagnosed with co-morbidities of the enrolled children are summarized in Table 1.
The median length of hospitalization was 2 days (IQR: 1, 3) and all children were discharged with no deaths. At hospital presentation, 38 (17%) cases had blood oxygen saturation (SPO2) level ≤ 92% and tachypnoea observed in 88 (38%). Nearly half of cases (109/230) received antibiotics in the 7 days prior to hospital presentation and all but three (227/230, 99%) received antibiotics during hospital stay. Twenty-four cases were diagnosed with pleural effusion and of these, 21 (88%) had pleural fluid drained: all 21 had microscopic purulence consistent with empyema.
There were 30 (13%) cases of definite bacterial pneumonia: 9 with bacteraemia, 15 with empyema, and 6 with both bacteraemia and empyema. Of the 21 pleural fluid samples from empyema cases, 1 was culture and PCR positive, and 9 were PCR positive (only) for Streptococcus pneumoniae, 1 each cultured methicillin-resistant Staphylococcus aureus, methicillin-sensitive Staphylococcus aureus, and Streptococcus pyogenes; and 1 sample was PCR positive for Mycoplasma pneumoniae. At least one respiratory virus was detected in NPS of 12 of the 30 cases with definite bacterial pneumonia. Of the remaining 200 cases, at least one virus was detected in nasopharyngeal swab from 118 (59%) cases including 98 with co-detection of respiratory bacteria. Among these 118 presumed viral pneumonia cases, 43 (36%) had RSV detected, 31 (26%) had rhinovirus, 21 (18%) had HMPV, 15 (13%) had influenza and 9 (8%) each had adenovirus and parainfluenza. No virus was detected in the nasopharyngeal swabs of 82 (41%) cases (other pneumonia) including 51 had detectable respiratory bacteria on NPS. The distribution of bacteria detected in NPS in three case groups of pneumonia are presented in Additional file 1: Table S1. The distribution of bacteria in NPS in three case groups were similar. Among cases in three groups, 53% of definite bacterial pneumonia cases, 40% of presumed viral pneumonia cases and 56% of other pneumonia cases received antibiotics before hospitalization.
The clinical features of cases and medical interventions are summarized in Table 2. Few differences in clinical symptoms and signs were observed across the different groups (Table 2). Fever (defined as temperature ≥ 38.0 °C) was more frequently observed in definite bacterial pneumonia than in presumed viral (p = 0.002) or other pneumonia cases (p < 0.001). Rhinorrhoea was more frequent in presumed viral pneumonia than in either definite bacterial pneumonia (p < 0.001) or other pneumonia cases (p < 0.001). Age-specific tachypnoea was also more common in presumed viral pneumonia than in definite bacterial (p = 0.08) or other pneumonia cases (p = 0.003). More definite bacterial pneumonia cases required intravenous fluid therapy than presumed viral (p = 0.02) or other pneumonia cases (p = 0.001). Furthermore, more than half (53%) of definite bacterial cases required both supplemental O2 and intravenous fluid, substantially higher than presumed viral (32%; p = 0.03) or other pneumonia cases (23%, p = 0.002) (Table 2). Definite bacterial pneumonia cases also had a greater median length of hospital stay (6.5 days, 9 days with empyema and 2 days without) than presumed viral (2 days) or other pneumonia (2 days) (p < 0.001 for each). The mean RISC severity score was 1.2 (range: 0, 5) for definite bacterial cases, compared to 1.0 (− 2, 5) for presumed viral and 0.8 (− 2, 4) for other pneumonia cases, respectively.
The median blood CRP concentration was more than 6 times higher in definite bacterial cases than in presumed viral (174 versus 24 mg/L; p < 0.001) and other pneumonia cases (174 versus 27 mg/L; p < 0.001). The CRP, WCC and ANC did not vary significantly between presumed viral and other pneumonia cases and between empyema and bacteraemia cases (Table 2, Additional file 1: Table S2). The blood biomarker values did not vary significantly between presumed viral cases with different viral pathogens detected (data not shown).
The AUC for CRP was 0.82 (95% CI: 0.73, 0.91) for discriminating definite bacterial from presumed viral pneumonia (Fig. 1a) and 0.81 (95% CI: 0.72, 0.89) for discriminating definite bacterial from presumed viral plus other pneumonias (Fig. 1b). For WCC, the AUCs were 0.63 (95% CI: 0.53, 0.74) and 0.65 (95% CI: 0.53, 0.76) for discriminating definite bacterial from presumed viral plus others pneumonias, and definite bacterial from presumed viral pneumonia, respectively (Additional file 2: Figure S1a, 1b). For ANC, the AUCs were 0.68 (95% CI: 0.58, 0.78) and 0.69 (95% CI: 0.58–0.79) for discriminating definite bacterial from presumed viral plus other pneumonias, and definite bacterial from presumed viral pneumonias, respectively (Additional file 2: Figure S2a, 2b). Based on these AUCs, we further assessed the sensitivity, specificity, PPV and NPV at CRP cut-offs of ≥ 40 mg/L, ≥ 60 mg/L and ≥ 100 mg/L, for differentiating bacterial from presumed viral plus other pneumonias, and definite bacterial from presumed viral pneumonias (Additional file 1: Table S3). CRP ≥ 40 mg/L, CRP ≥ 60 mg/L and CRP ≥ 100 mg/L cut-off had sensitivity of 83, 75 and 67%, respectively for differentiating definite bacterial pneumonia from presumed viral pneumonias. From the Youden index, the optimal CRP threshold of ≥72 mg/L was found to discriminate definite bacterial from presumed viral plus other pneumonias with sensitivity 75% (95% CI: 55, 89), specificity 82% (95% CI: 76, 87), PPV 38% and NPV 96%; for discriminating definite bacterial from presumed viral pneumonias the sensitivity was 75% (95% CI: 55, 89), specificity 84% (95% CI: 76, 90), PPV 53% and NPV 93% (Table 3).
Significant differences in symptoms and signs were then included to assess the impact on the diagnostic performance of the algorithm (Table 3; Additional file 1: Table S3). The combination of CRP (≥72 mg/L) with either the presence of fever or absence of rhinorrhea, improved the specificity and PPV for differentiating bacterial pneumonia from presumed viral plus other pneumonias compared to the CRP alone, with little loss of sensitivity and NPV. While 73% of cases with definite bacterial pneumonia had both fever and elevated CRP (≥72 mg/L), only 11% of presumed viral plus other pneumonias and 10% of presumed viral pneumonias did. Similarly, 65% of definite bacterial pneumonia had elevated CRP (≥72 mg/L) and the absence of rhinorrhea, compared to 7% of presumed viral and other pneumonias, and 2% of presumed viral pneumonias. The PPV for the combination (CRP ≥72 mg/L + fever) and (CRP ≥72 mg/L + absence of rhinorrhea) was 48 and 59% for discriminating definite bacterial from presumed viral plus other pneumonia, and was 63 and 87%, respectively, for discriminating definite bacterial from presumed viral pneumonia, respectively (Table 3).
The number of cases of virus infection diagnosed each month was higher in the winter months and lower in the summer months (Fig. 3).