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To this time there are no studies available concerning therapeutic interventions. This is mainly due to the retrospective nature of most investigations. Further, no causal association between WUPyV and respiratory disease has been shown yet. As the need for therapeutics is driven by associating infections with disease, studies on therapeutic interventions are not to be expected in the near future. For BK virus associated nephropathy in renal transplant patients, reduction of immunosuppressive therapy is recommended if possible. In the case of progressive renal dysfunction fluoroquinolones (antibacterials), intravenous immunoglobulines, leflunomide, and – in otherwise refractory cases – cidofovir could be administered. For JC virus caused progressive multifocal leukoencephalopathy (PML) no specific therapy exists. In HIV-positive patients HAART induced improvement of cellular function may lead to an at least temporary improvement. Failure of treatment approaches with interferon alfa-2b, cytarabine, cidofovir, and topotecan has been documented.
Antibiotics were given to all of the patients empirically before and after confirmed diagnosis. There is currently no formally approved antiviral therapy for the treatment of severe life-threatening adenovirus infection in China. Acyclovir, ganciclovir or ribavirin is commonly chosen by the physician to treat adenoviral infection. In this study, all of the fatal patients were administered antiviral drugs—one was treated with ganciclovir, two with acyclovir and one with ribavirin. In surviving patients, 50% were treated with antiviral drugs—three with ganciclovir, one with acyclovir and one with ribavirin. All of the fatal patients (4/4) were complicated with ARDS and admitted to the ICU. They needed mechanical ventilation, and three of them received ECMO to maintain oxygenation. For surviving patients, one of them (1/10) was admitted to the ICU due to ARDS, and had mechanical ventilation and ECMO; one patient with respiratory failure was treated with non-invasive ventilation, and one patient was treated for myocarditis. The myocarditis patient presented with peak levels of creatine kinase isoenzyme (CK-MB) and cardiac troponin I (CTNI) on day 7–8 after disease onset, and eight days later, with viral load going down to negative, CK-MB and CTNI went down to normal levels in parallel (Fig 4).
For the four fatal patients, the times of death were on days 14, 16, 22 and 28 after disease onset, respectively. There was no significant difference in length of stay in-hospital between the two groups (13.5±6.5 days vs 13.3±9.2 days, p = 0.969) (Table 2).
Despite extensive research, no agent has been approved for prevention and/or therapy of rhinovirus-induced diseases so far. Ruprintrivir selectively inhibits HRV 3C protease and shows potent, broad-spectrum anti-HRV activity in vitro . Ruprintrivir nasal spray (2% solution) prophylaxis reduced the proportion of subjects with positive viral culture by 26% and reduce viral titers, but did not decrease the frequency of colds. HRV RNA synthesis during replication can be blocked by deoxyribozymes, morpholino oligomers, and small interfering ribonucleic acids. The novel antiviral therapies that have been discovered recently, may one day add significantly to the armamentarium of antiviral agents, against respiratory viral infections in asthmatic children.
Maternally-derived RSV neutralizing antibodies help to protect infants against RSV hospitalization. Palivizumab, a humanised monoclonal antibody against the RSV fusion protein is effective against RSV and wheezing in children and reduces hospitalization in high-risk individuals. RSV prophylaxis with palivizumab significantly reduced the relative risk of subsequent recurrent wheezing in nonatopic premature infants. Motavizumab is another monoclonal antibody against RSV, with an approximately 20-fold increase in ability to neutralize RSV and 100 fold increase in ability to reduce viral titers compared to palivizumab. Motavizumab was also found to be superior to palivizumab in reducing outpatient medically attended lower respiratory illness by 50%.
This was a prospective observational study analyzing mini-bronchoalveolar lavage (mini-BAL) samples of invasive mechanical ventilated patients from two polivalent Intensive Care Units (ICUs) of Lisbon district, in Portugal. Patients were divided in two groups; WORI group included patients admitted for causes other than respiratory infection and not receiving antibiotic therapy (respiratory symptoms were excluded at time of admission, namely cough and sputum; chest x-ray was performed in all the patients to exclude lower respiratory infection. It was not possible to obtain reliable information about the presence of respiratory symptoms before admission nor about influenza vaccination history). WRI group included patients admitted for acute respiratory infection and on antibiotic therapy. All patients enrolled in the study required endotracheal intubation to treat their acute respiratory failure.
Exclusion criteria were age less than 18 years, pregnancy, immunosupression and antiviral therapy on admission. The participants, or their legal representatives, were informed about the study objectives and their signed consents were obtained previously to the sample collection. The Ethic Committees of both participating centers approved the study protocol.
Patient demographics, comorbidities, Acute Physiology and Chronic Health Evaluation (APACHE) II score and Simplified Acute Physiology Score (SAPS) II, admission diagnosis and ICU clinical outcome were recorded.
Sample collection was performed with a Combicath® kit, between December 2016 and March 2017.
The pre-publication history for this paper can be accessed here:
Nine patients were treated for their hMPV infections (median age 9 years; range, 5 months–19 years). These patients included 5 HSCT recipients, 2 patients with hematologic malignancy, and 2 patients with solid tumors. Indications for HSCT included aplastic anemia (n = 2, 22%), SCID (n = 2, 22%), and Ewing sarcoma (n = 1, 11%).
Eight (89%) of these treated patients had fever, 6 (75%) had cough, and 7 (78%) had abnormal chest imaging. Five (56%) had a copathogen identified. Five (56%) were hospitalized in the ICU, and 5 (56%) received supplemental oxygen. Five (56%) patients received both ribavirin and IVIG, 2 (22%) received ribavirin alone, and 2 (22%) received IVIG alone.
Of the 5 HSCT recipients, 3 (60%) had hMPV detected prior to transplant (median time prior to transplant: 43 days; range, 93–21 days), and 1 detected 11 days after transplant. Treatment with ribavirin and IVIG was initiated a median of 5 days after hMPV diagnosis (range, 2–46 days), and several patients received multiple courses of ribavirin and IVIG. Treatment with ribavirin alone (n = 2) was initiated 2 and 4 days after diagnosis, respectively. Of the 7 patients who received ribavirin, 6 (86%) received inhaled ribavirin at a dose of 2 g 3 times daily for a 5-day course, and 1 (14%) received an 11-day course of intravenous ribavirin.
We investigated the relationship between the virological factors and clinical outcomes in a cohort of 14 hospitalized adults with AdV pneumonia. Our results suggest that a higher initial viral load (108 copy/ml) in the respiratory tract samples on day 5–7 after disease onset is a predictor for fatal clinical outcome. We also reported that viremia is common and sustained viremia for 14 days or more may be associated with mortality
The pathogenesis of mortality in Adv pneumonia is still unknown. Virological factors, e.g., a new strain with new genetics, viral load, slow virus clearance and systemic infection with viremia likely play key roles for severe Adv [2–8]. However, no study has evaluated the viral shedding history among immunocompetent adults with AdV pneumonia. This study first monitored the consecutive viral load in respiratory tract samples and whole blood samples. Our previous clinical study demonstrated that on day 5–7 after disease onset, the peak stage of illness presented for patients with shortness of breath or severe dyspnea. Again, in this study, we showed that the viral load on day 5–7 could also provide an insight into the severity of illness. Evidence even proved that a higher level of viral load in respiratory tract samples on day 5–7 after disease onset was significantly associated with fatal outcome.
We have noted that viremia is quite common on day 5–7 after disease onset, when 9 out of 11 (81.8%) patients had viremia. Adenovirus viremia has been found in hematopoietic stem cell transplantation recipients and associated with AdV disease. Compared with previous reports of viremia and clinical outcomes, another novel finding is that we demonstrated that fatal outcomes could be predicted by sustained viremia, but not by viremia itself. In this study, we showed that 100% (4/4) of patients in fatal cases presented with viremia on day 12–14 after disease onset, compared with 60% (p = 0.126) of the patients in surviving cases.
In one case, as shown in Fig 2, even though the patient presented with a higher viral load (108.32 copies / ml) in tracheal aspiration, which may be associated fatal outcome, his clinical manifestation recovered gradually with a downward trend in the viral load in respiratory tract and whole blood samples. Compared to this case in Fig 3, the patient described in Fig 3 not only had a higher viral load (109.25 copies/ml) in tracheal aspiration but also presented with sustained elevated viral copies, especially in whole blood. Shike et al. also reported a 6-month-old infant with systemic infection by adenovirus who had high-level viremia and showed reduction in viral load paralleling her clinical recovery. Therefore, in severe cases, dynamic monitoring of viral shedding, especially in whole blood, could help predict the clinical outcome. Patients might have bad outcomes if the viral load in whole blood does not present a significant downward trend around two weeks after disease onset.
There is currently no formally approved antiviral therapy for the treatment of severe life-threatening adenovirus infection in China. Cidofovir is considered the medicine of choice for severe infection in immunocompromised patients. Cidofovir is not available in most hospitals in China, including our hospital. Acyclovir, ganciclovir or ribavirin is usually prescribed in China. In this study, antiviral drugs were administered in all of the fatal cases—one patient was treated with ganciclovir, two with acyclovir and one with ribavirin. In surviving patients, 50% were treated by antiviral drugs—three with ganciclovir, one with acyclovir and one with ribavirin. The choice of the antiviral medicine was decided by the patient’s physician. As none of these three medicines have been confirmed to be effective for AdV infection, the relationship between viral shedding and clinical outcomes in this study was not associated with anti-adenoviral treatment effect.
Our study has two limitations. As AdV 55 was the most common infection type (10/14, 71.4%) in this study, results might be more significant in AdV 55-associated pneumonia and might not be generalizable to other types of AdV pneumonia. In our previous study, adults infected with AdV 55 were 10 years older and presented with higher PSI scores compared with adults infected with other serotypes. Another limitation of this descriptive work may be the small number of analyzed patients, especially in the group of fatal cases (n = 4). More cases are needed to confirm our findings.
In conclusion, our data provide new insight into the virology of AdV pneumonia. A higher initial viral load (108 copy/ml) in the respiratory tract on day 5–7 after disease onset and sustained viremia for 2 weeks or more may be associated with fatal clinical outcomes.
NPA sample (200 μl) from the patient was subjected to total nucleic extraction after addition of internal control bacteriophage MS2 (20 μl) using the MagNA Pure LC Total Nucleic Acid Isolation kit (Roche Diagnostics, Germany) on Magna Pure LC 2.0 platform, following the manufacturer's instructions. The method is based on magnetic-bead technology. The procedure included cellular destruction, nucleic acid binding on beads, and washing steps to remove cellular and purified nucleic acid elution. Extracted nucleic acids were eluted in 50 µl of elution buffer and stored at −80°C for RVP FAST assay.
No specific antiviral or licensed vaccine is available for a CoV that infects humans, but a range of candidates exist. Even if MERS-CoV infection is rare, transmits poorly, and does not evolve to become a pandemic threat, it serves in a useful role to drive vaccine research of other CoVs, both current and yet to emerge. For cases in healthcare facilities, improving hand hygiene, the use of PPE (gloves, gown, respiratory, and eye protection), and surface cleaning can help disrupt transmission, as can rapid triage of febrile patients with respiratory signs and symptoms. To prevent MERS-CoV infection from dromedary camels, precautions include avoiding contact with camel nasal secretions, cooking camel meat, and pasteurising camel milk until further studies better quantify the risk attached to each of these potential pathways.
Vaccines to prevent CoV disease require both humoral and cellular immunity. Because airway immune responses may be key to preventing the establishment of human MERS-CoV infection, localised deposition of an aerosolised vaccine could prove useful. A number of vaccine platforms and payloads have proceeded although progress has been challenged by the need for animal models that suitably reconstitute human lower respiratory tract disease to show evidence of any preventative effect. Some candidates have progressed to clinical trials. The spike protein and RBD elicit neutralising antibody responses and have been employed as the payload for a number of platforms including DNA vaccines, modified vaccinia virus Ankara, measles virus, and human- and chimpanzee-adenovirus-based vectors. There are also Venezuelan equine encephalitis replicons expressing nucleocapsid, nanoparticles, and structural and non-structural deletion mutants of MERS-CoV.
Vaccination of camels is likely to be the most rapid, least expensive, and best intervention for preventing rare spillovers that then become amplified by humans in healthcare settings. Successes have been reported, but the approach is challenged by the problem that camels are naturally reinfectable with MERS-CoV, even in the presence of a high titre of neutralising antibodies. To date, camel vaccines reduce viral load but do not prevent virus shedding. Human vaccines could target the occupational at-risk groups, which include healthcare, farm, barn, market, and slaughterhouse workers. More widespread application of a MERS vaccine at this time does not seem warranted.
The rarity of seropositive donors, sometimes low antibody titres, and a lack of clinical evidence have made the use of convalescent sera from recovering MERS patients a possibility for treatment, but one with significant limitations. Instead, human monoclonal antibodies targeting the RBD and polyclonal antibodies may provide treatment options for those at risk of severe outcomes. Clinical trials are awaited.
Early control of viral replication is important and administration of interferon (IFN) β1b or a ribavirin and IFN α2b combination within hours initially showed promise. Their practical use in humans is challenging because, if not infected while in a healthcare setting, humans usually present for care with well advanced disease. Combined treatments which reduce viral replication and the host immune response to it are likely to be valuable developments.
A wide range of repurposed or novel potential antivirals including polymerase, nucleotide synthesis and protease inhibitors, and fusion-inhibiting peptides have been investigated. Corticosteroid use is not recommended for acute respiratory distress syndrome. Comparative studies and randomised controlled trials are mostly lacking.
A protected mini-BAL (with a double catheter, Combicath® kit (Plastimed, Saint-Leu-La Forêt, France)) was performed on the first 24 h after the tracheal intubation and invasive mechanical ventilation. A combicath was introduced blindly through the oro-tracheal tubeuntil its end on the lower third of the trachea and wedged in the bronchial tree. Mini-BAL samples were obtained by intilling 2 mL of room temperature saline solution (0.9%), followed by gentle suction after the infusion of each aliquot. Samples were stored at − 80 °C until processed.
On admission, a nasopharyngeal swab was collected from children complaining of respiratory symptoms or fever without a focus. Samples were sent, as soon as possible, to the Department of Laboratory Medicine where a multiplex PCR test for respiratory viruses was conducted. The commercially available AdvanSure™ RV real-time PCR kit (LG Life Sciences Ltd., Seoul, Korea) was used to detect ADV, influenza A and B viruses, RSV, parainfluenza virus, rhinovirus, coronavirus, human metapneumovirus, and human bocavirus. A positive PCR result for ADV confirmed an ADV infection. If the PCR result was positive for only ADV, the child was assigned to the ADV group, and if the PCR result was positive for two or more viruses including ADV, the child was assigned to the coinfection group.
Upper respiratory tract infection (URTI) included acute pharyngitis, pharyngoconjunctival fever, and acute otitis media, while lower respiratory tract infection (LRTI) included acute bronchiolitis, acute bronchitis, and pneumonia.
We collected 2 ml of nasopharyngeal aspirate from each participant and stored the samples at −70°C until analysis. NPA collection was performed by trained nurses. The catheter was inserted into the nostril to a depth of 5 to 7 cm and drawn back while applying gentle suction with a syringe.
A 17-month-old Latvian boy was admitted to the Children’s Clinical University Hospital of Riga, Latvia, on the seventh day of illness in January 2015. He presented with a history of rhinorrhea and cough for 6 days and fever (axillar temperature 39.0 °C) for the last 2 days prior to admission. Due to severe respiratory distress, he was immediately transferred from the regional hospital to our intensive care unit.
On admission, his respiratory rate was 44 breaths/minute (reference 20–30), heart rate 146 beats/minute (reference 80–130), oxygen saturation 99% (with an oxygen flow of 5 liters/minute via face mask), and axillary temperature 38.7 °C. Auscultation of his lungs revealed bilateral wheezing and crepitation with severe intercostal and subcostal recessions. The other organ systems were without pathology. Due to the severe respiratory distress, tracheal intubation was performed.
The child had been born full term as the seventh in the family. He had no known underlying illness, history of previous hospitalizations, or severe acute illnesses. He had been fully immunized according to the national immunization scheme.
On admission, his white blood cell (WBC) count was 30.6 × 103/μL with 66.9% of granulocytes (in absolute numbers 20.6 × 103/μL), hemoglobin 12.4 g/dL, and platelet count 321 × 103/μL. His C-reactive protein (CRP) was 5.09 mg/L. A chest radiograph showed infiltration of the upper lobe of his right lung (Fig. 1).
At the time of admission, a nasopharyngeal swab (NPS) tested negative by direct immunofluorescence (IMAGEN™ OXOID, UK) for antigens of RSV, influenza virus A and B, parainfluenza virus types 1–3, and adenovirus. Bacterial blood cultures were negative. NPA, blood, and stool samples were collected for HBoV1 molecular diagnostics and serology.
NPA tested by qualitative multiplex PCR (Seegene Respiratory Panel, South Korea) was negative for: influenza virus A and B; RSV A and B; flu A types H1, H1pdm09, and H3; adenovirus; enterovirus; parainfluenza virus types 1–4; metapneumovirus; rhinovirus; and coronavirus types NL63, 229E, and OC43. However, the NPA tested by qualitative multiplex PCR was positive for HBoV1. NPA, whole blood with corresponding cell-free blood plasma, and stool samples underwent qualitative PCR for HBoV1 NS1 DNA, as described. An HBoV1-containing plasmid was used as a positive control in PCR. All these samples were HBoV1 DNA positive. Upon re-examination by quantitative PCR (qPCR) (Human bocavirus genomes, Standard kit, Genesig, Primerdesign Ltd., UK), the copy numbers in NPA and stool were high, 5.7 × 105 per μg DNA in NPA and 1.4 × 108 per μg DNA in stool. The viral load in blood was 21 copies/μg DNA, but in cell-free blood plasma the viral load was under detection level.
To prove that the HBoV1 infection was actively ongoing, HBoV1 transcription in PBMCs was applied. Total ribonucleic acid (RNA) was extracted from PBMCs using TRI Reagent® solution according to the manufacturer’s instructions (Thermo Fisher Scientific, USA). The extracted RNA was quantified spectrophotometrically and analyzed by electrophoresis in a 1% agarose gel. RNA was treated with DNase (TURBO DNA-free™ Kit, Thermo Fisher Scientific, USA) before the synthesis of complementary DNA (cDNA) by the reverse transcriptase (RT) using RevertAid™ First Strand cDNA Synthesis Kit (Thermo Fisher Scientific, USA). The β-actin gene sequence was detected by PCR to assess the quality of synthesized cDNA (Fig. 2).
HBoV1-specific cDNA was detected by PCR targeting the HBoV1 NS1 gene as described by Sloots et al., in 2006, followed by electrophoretic visualization of the amplification products in a 1.7% agarose gel (Fig. 3). The same DNase-treated RNA sample but without the RT step, served as a negative control in both the β-globin and HBoV1 PCRs to make sure that there was no contamination with DNA.
Biotinylated virus-like particles (VLPs) of the recombinant major capsid protein VP3 were used as antigen in enzyme immunoassays (EIAs) for detection of HBoV1-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) in our patient’s plasma sample [23, 24]. For removal of possible cross-reacting heterologous human bocavirus 2 (HBoV2) and human bocavirus 3 (HBoV3) IgG, non-biotinylated VLPs in competition assays were used as described. Our patient’s plasma sample was positive for both HBoV1-specific IgM and IgG antibodies.
Because of the right lung upper lobe infiltration and increased WBC initially, the child was treated with intravenously administered ceftriaxone 350 mg twice a day for 7 days and per-oral oseltamivir 30 mg twice a day (due to influenza season). Oseltamivir was discontinued after 3 days due to the negative influenza virus A and B antigen findings. Extubated on day 3, our patient was brought to the Department of Paediatrics, where intravenously administered ceftriaxone was continued, inhalations via nebulizer with salbutamol and budesonide were begun and pulmonary rehabilitation started. During the next 10 days, the child’s general condition improved, his body temperature was normal, lung sounds were without the pathology, and no additional oxygen was needed. During the hospitalization, poor weight gain was observed for our patient; therefore, additional diagnostic tests were done and his hospitalization length increased. On day 17 of hospitalization, he developed a new episode of fever for 2 days. The second NPS tested negative for RSV, and influenza virus A and B; however, self-limiting viral upper respiratory tract infection was suspected and he was treated with intravenously administered rehydration and ibuprofen 70 mg for these 2 days. Due to the very low socioeconomic status of the family, he was kept in the hospital mainly for observation, although his general condition was good. On day 30 he developed a new episode of fever, cough, and wheezing lasting 6 days. In this episode, LRTI was diagnosed based on the clinical symptoms and he was treated with nebulized salbutamol and budesonide.
After 46 days of hospitalization he recovered completely from HBoV1-associated acute bilateral bronchiolitis with right-side pneumonia and a subsequent hospital-acquired upper and LRTI and was discharged.
The pathogenesis of hMPV infection is strongly affected by bacterial coinfections with pneumococcus. One study has shown that administration of a conjugate pneumococcal vaccine is sufficient to reduce the incidence of hMPV infection of the lower respiratory tract and the incidence of clinical pneumonia in both HIV positive and negative patients. These finding suggest that the incidence of hospitalizations in hMPV infections may be decreased by vaccination with a conjugate pneumococcal vaccine. Another case report of severe respiratory failure was found to be caused by coinfection with hMPV and Streptococcus pneumonia in a 64 year old patient. Both in vitro and in vivo studies have shown that infection with hMPV facilitates adhesion of pneumococcal bacteria, which may provide an explanation for the coinfection with pneumococcal strains and hMPV.
Viral coinfections between hMPV and RSV have been reported, but remain a contentious issue. The typical seasonal overlap of the two viruses has been suggested to promote viral coinfection. One study reported a 10-fold increase in risk of admission to an intensive care unit in pediatric patients coinfected with RSV and hMPV and associated the dual infection as capable of augmenting severe bronchiolitis. Other studies do not support this finding and further report a decreased correlation between hMPV-RSV coinfections and hospitalization and additionally lists dual infection, along with breastfeeding, as having protective effects.
Three patients (5%) died of respiratory failure related to hMPV pneumonia. Two of these deaths occurred in HSCT recipients who were diagnosed with hMPV prior to transplant (Figures 1 and 2B: Patients 2 and 3). One HSCT recipient had not engrafted at time of death, while the other engrafted the day prior to death. Both were treated with ribavirin and IVIG. The third death occurred in a patient with ALL and secondary acute myelogenous leukemia on salvage chemotherapy who did not receive hMPV-specific treatment (Figure 2B: Patient 5). HMPV was considered to be a contributing factor to her death, though the primary cause of death was thought to be progression of ALL. The median time to death was 37 days (range, 37–64 days).
HBoV1 infection may cause life-threatening acute bronchiolitis, as this pediatric case demonstrates. The diagnosis of acute HBoV1 infection was proved by the presence of HBoV1-specific IgM and DNA in cell-free blood plasma as well as HBoV1 mRNA in PBMCs, whereas no other viruses or bacteria were found by PCR and culture, respectively.
Viral infections of the upper and lower respiratory tract are among the most common illness in humans. Children and infants bear the major burden of infection, typically presenting with 5 to 6 episodes annually. These infections are often associated with significant patient morbidity and related mortality. For this reason, URTIs and LRTIs represents the leading cause of death in children younger than five years of age worldwide; this accounts for approximately 4 million deaths annually. Acute respiratory tract disease is the leading cause of hospitalization in children and febrile episodes in infants younger than three months of age.
Bacteria only represent approximately 10% of all upper respiratory tract infections with the subsequent 90% of infections caused by respiratory viruses. Despite the viral aetiological origin of most respiratory infections, antibiotics are often prescribed in the treatment of such diseases, exacerbating antibiotic abuse. The morbidity and fiscal implications associated with respiratory infections are significant, with approximately 500 million cases reported in the United States alone each year with subsequent direct and indirect costs to the US economy estimated at $40 billion annually. The burden of respiratory tract infections is increased in patients with chronic comorbidities or clinical risk factors including asthma, chronic obstructive pulmonary disease (COPD), young, elderly and immunocompromised.
The viruses primarily associated with upper respiratory tract infections commonly include rhinoviruses, enteroviruses, adenoviruses, parainfluenza viruses (PIV), influenza viruses, respiratory syncytial viruses (RSV) and coronaviruses. In recent years six new human respiratory viruses have been reported including human metapneumovirus (hMPV), bocavirus and four new human coronaviruses including Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63), HCoV-HKU1 and Middle East Respiratory Syndrome coronavirus (MERS-CoV). This review will detail these newly discovered and emerging respiratory viruses.
The study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. The study was conducted in accordance with the Declaration of Helsinki. Verbal consent was obtained from the participants and written consent was obtained from their parents or legal guardians.
SRTI was assessed according to respiratory failure confirmed by an abnormal blood gas analysis result (based on the potential of hydrogen, partial pressure CO2, partial pressure O2, an oxygen saturation level of approximately 90% or less and the need for oxygen therapy) or by being a patient in intensive care unit (ICU) for mechanical ventilation treatment.
The discovery of novel respiratory viruses has the potential to diminish the diagnostic gap for respiratory tract infections. Creer and co-workers, who omitted the recently identified respiratory viruses in their study on adults, reported a diagnostic gap of 31%. The share of specimens from children negative for any respiratory pathogen investigated was 22% when hMPV, HBoV, and HCoV-NL63 were included. No study included the novel polyomaviruses or herpes viruses until now. Thus, a further reduction of the respiratory tract infections of unknown origin seems reasonable. However, a substantial gap is remaining leaving sufficient room for additional respiratory viruses to be discovered in the future.
So far it has not been finally proven, if WUPyV is a real causative agent for respiratory diseases. Association of virus detection with previously unexplained respiratory disease led to the tempting idea of WUPyV representing a new etiologic agent, particularly in cases where no other respiratory tract pathogen could be identified. Furthermore, the association of mouse pneumotropic polyomavirus with intestinal pneumonia and significant mortality indicates that polyomaviruses have the capacity to be respiratory tract pathogens.
Many studies correlating the detection of WUPyV with the incidence of respiratory symptoms argue for this hypothesis, but it remains difficult to prove as asymptomatic control groups have not been investigated sufficiently. Additionally, the studies including control groups report dissenting findings. However, in two studies asymptomatic individuals display a lower frequency of virus detection compared to symptomatic patients. One of these is the only prospective study available.
The difficulty to prove WUPyV to be a respiratory pathogen may be due to the fact that most studies available so far try to correlate the virus with respiratory tract disease in general. In case of WUPyV being the causative agent of a particular entity of respiratory tract disease, inclusion of patients displaying any kind of respiratory disease may bias the investigation. Focussing on a single entity of respiratory disease proved successful for HCoV-NL63, which was shown to cause croup.
No association of WUPyV viral loads and clinical symptoms could be observed so far, and co-infections with other viruses were described frequently. This weakens the hypothesis of WUPyV being a respiratory tract pathogen. However, collection of samples was not performed by means of a standardized protocol among the various groups or at a defined time point, after onset of symptoms. As viral loads decrease during the acute phase of infection, the combination of longitudinal data from different time points in one analysis may bias the correlation of viral loads and symptoms. Furthermore, detection of co-infection does not exclude pathogenic potential for WUPyV, as early childhood is characterized by subsequent episodes of respiratory infections. Co-detection of the declining pathogen responsible for the last episode of respiratory disease and the pathogen responsible for the present, acute disease has to be expected. Only determination of the viral load kinetics would allow defining the clinical impact of a detectable microorganism.
The large T-antigen of WUPyV contains binding sites for the RB protein and p53. Thus, tumourigenic potential cannot be excluded. However, the association of WUPyV with other diseases, particularly tumour diseases has not been sufficiently investigated yet.
Taken together, the currently available data neither prove nor deny WUPyV to be a respiratory tract pathogen. Several scenarios may describe the role of the virus best. WUPyV may be
part of the endogenous viral flora without pathogenic potential;an opportunistic pathogen with pathogenic potential in the respiratory tract under conditions still to be defined;a pacemaker for secondary infections;a viral pathogen using the respiratory tract only as an entry route to reach the final target cell; infection of this cell type is the basis of a disease not related to the respiratory tract.
To reach a final conclusion more powerful, controlled studies need to be performed prospectively. However, retrospective analysis of age- and time-matched control populations also permits conclusions if the data collected at the time are related to respiratory illness. Ideally, prospective studies would be carried out in a multicenter-design including control groups concentrating on the correlation of WUPyV with single entities of respiratory tract diseases. Criteria for inclusion of specimens have to be comparable, as well as the time point and the protocol for extraction of specimens. All known or suspected respiratory tract pathogens should be included and follow-up investigations should be performed. The detection method of choice would be quantitative PCR to allow discrimination between colonisation and productive infection. Additionally, serological investigations should be included to show that the patients seroconvert in response to an infection. The study participants should be evaluated before enrolment. Beside investigation of respiratory tract disease, the cell type hosting the persisting virus has to be identified and a possible association with tumour diseases has to be investigated.
In total, 105 children were diagnosed with an ADV infection during the study period. The median age at enrollment was 29 months (range: 0-131 months), and 60 (57.1%) children were males. On admission, 104 (99.0%) children complained of fever, and the fever persisted for a median of 5 days (range: 0-13 days) [starting 3 days (range: 0-10 days) before admission and persisting until 2 days (range: 0-5 days) after admission]. Among the local symptoms presented on admission, respiratory symptoms (87 children, 82.9%) were the most frequent, followed by gastrointestinal (24 children, 22.9%) and ophthalmologic (18 children, 17.1%) symptoms. Among gastrointestinal symptoms, diarrhea (17 children, 70.8%) was most frequent, and vomiting (11 children, 45.8%) and abdominal pain (7 children, 29.2%) followed. Febrile seizures occurred in four (3.8%) children. Five children (4.8%) showed fever without localizing signs. URTI and LRTI were diagnosed in 56 (53.3%), and 32 (30.5%) children, respectively. Thirteen (12.4%) children had underlying medical conditions. Eleven (10.5%) children were born prematurely and eight (7.6%) of them also had a previous history of bronchopulmonary dysplasia (BPD); one child had an underlying congenital hypotonia and had experienced recurrent pneumonia since birth; and one child received corrective surgery for esophageal atresia and experienced recurrent respiratory tract infections since the surgery.
Five (4.8%) of the children enrolled in the present study received oxygen therapy, one (1.4%) child in the ADV group and four (12.5%) children in the coinfection group. The child in the ADV group was diagnosed during hospitalization for preterm birth and neonatal respiratory distress syndrome (RDS). He was admitted to the neonatal ICU at birth, received ventilator care and surfactant replacement therapy, and was extubated on hospital day 6. However, fever and apnea developed on hospital day 25, and he received ventilator care again. ADV infection was diagnosed at this time, and he was extubated on hospital day 36. The four children in the coinfection group received oxygen therapy for less than 3 days: two children were born prematurely and had a history of BPD, one child had underlying congenital hypotonia, and the remaining one child was previously healthy.
The study followed the Declaration of Helsinki on medical protocol and ethics. The Ethics Committees of both Shandong Medicinal Biotechnology Centre and Qilu Children's Hospital of Shandong University approved the study. Written informed consent was obtained from the next of kin of the participants.
We found that viral infections were often neglected during this population-based “real life” study of suspected septic patients. The study was performed during the winter period, referred to as “the flu season”, when respiratory viral infections are most prevalent. This should have resulted in increased clinical suspicion. Yet, during the first four weeks of the influenza epidemic, very few clinical samples are requested. In this material, a viral respiratory infection was initially suspected by clinicians in only 30% of patients with viral findings by multiplex PCR. This was especially true when CRP was over 100 mg/L, or if there was a new infiltrate on the chest X-ray indicating pneumonia. This underestimation may lead to nosocomial spread or outbreaks of viral respiratory infections, as we have previously experienced in our own hospital. It may also lead to overuse of antibiotics, as well as underuse of antivirals, especially in risk groups that might benefit from such treatment.
As in a comprehensive study on bacterial–viral respiratory tract illness over three winter seasons by Falsey et al. in 2013, influenza A virus was the most common viral finding, appearing in study samples almost two weeks earlier than in clinical samples. In only 35 of 96 cases of influenza A virus infection (36%) was influenza virus initially suspected as sole cause or contributing factor to the acute illness.
Respiratory syncytial virus and human metapneumovirus may cause critical respiratory illness and pneumonia, not only in children, but also in elderly. For example, human metapneumovirus was found to be the causative agent in an outbreak of pneumonia among elderly at an institution in the Netherlands. In this study, human metapneumovirus was a slightly more common finding than respiratory syncytial virus, especially in patients with long history of fever and respiratory tract congestion, combined with radiological signs of pneumonia.
Nasopharyngeal culture is generally discouraged or not recommended for etiological diagnosis of pneumonia. However, in a Swedish study by Strålin et al. in 2006, there was a good correlation between nasopharyngeal findings of these bacteria and the etiology of pneumonia, as has been seen in previous Swedish studies. In our study of patients in the emergency department suspected to be septic, there was a strong correlation between nasopharyngeal findings of S. pneumoniae or H. influenzae and X-ray findings of a new infiltrate, indicative of pneumonia. More so, these bacteria were not found in the nasopharynx of any of the 210 patients with a non-respiratory infection or no infection, and they were rarely found in patients with a respiratory tract infection but not pneumonia. The study results imply that nasopharyngeal findings of S. pneumoniae and H. influenzae in sepsis patients should be considered carefully for patient treatment. A recently published paper by Bjarnason et al. in 2017 demonstrates a good correlation between real-time PCR findings of S. pneumoniae or H. influenzae to pneumonia diagnosis in adults, which also builds support for a clinical relevance of these upper respiratory bacterial findings.
Co-infections of bacteria and respiratory viruses, mainly S. pneumoniae and influenza A or respiratory syncytial virus, are found in 3–40% of patients with CAP, depending on diagnostic methods used, with the higher end reflecting studies in which nasopharyngeal culture is included for etiological diagnosis [1, 2]. Using nasopharyngeal sampling only, we found indications of viral-bacterial co-infections in 28 of 137 (20%), a proportion we believe to be an underestimation. As in the study by Falsey et al. in 2013, S. pneumoniae was the bacteria most often associated with pneumonia and a viral co-infection. As many as 75% of patients with pneumonia and S. pneumoniae in the nasopharynx were positive for a respiratory virus, mainly influenza A virus, but also human metapneumovirus. The two youngest patients, with pneumonia and severe sepsis, aged 37 and 42 years respectively, were both positive for S. pneumoniae and human metapneumovirus in the nasopharynx. No other pathogens could be demonstrated by routine cultures.
In the clinical setting it is often difficult to determine whether a patient with respiratory symptoms has a viral infection, a bacterial infection, or a mixed viral-bacterial infection. No constellation of clinical symptoms, vital signs, biomarkers (such as white blood cell count, C-reactive protein, or procalcitonin) have adequate sensitivity and specificity. New tools to improve predictions of patient benefit from antibiotic treatment are urgently needed. Recently, whole blood analysis for the identification of host gene activation profiles has been able to discriminate viral infections from bacterial infections with high accuracy in severely ill infants, as described by Herberg et al. in 2016. In adults with lower respiratory tract infections, a similar technique seems able to discriminate viral from bacterial infections much better than procalcitonin, as shown by Suarez et al. in 2015. In the same study mixed viral-bacterial infections also elicited a characteristic gene activation profile.
Our study supports increased testing for respiratory viruses in patients believed to be septic, especially those presenting with respiratory tract symptoms. With current technology, results can be obtained within a few hours and have an impact on clinical decisions and patient logistics in the emergency department. Cost effectiveness should be investigated. A viral diagnosis may not only lead to fewer admissions and less antibiotic treatment if bacterial pneumonia is suspected or demonstrated, but may also decrease viral exposures for admitted patients. Patients with influenza A or B may benefit from antiviral treatment alone or in conjunction with antibacterial treatment, if bacterial pneumonia is suspected or demonstrated, perhaps even reducing viral contagiousness. Even in neutropenic patients, a viral finding and a favorable outcome in the first few days may safely allow for discontinuation of antibiotic treatment.
This study has several limitations. It is a single-center study performed during one winter period only. The study was primarily not an etiological study of respiratory tract infections. We did not take ongoing antibiotic treatment into account. Only routine sampling from the nasopharynx was performed, albeit using a flocked swab for better yield. If sputum or nasopharyngeal aspirates had been analyzed with molecular techniques, we would have expected a higher yield for both bacteria and viruses [2, 30]. A further weakness is the open inclusion based on clinical suspicion of sepsis only, without specific criteria. Yet another was the subjectivity involved in deciding the relevance of the findings. What role do the viral findings play, both alone or in conjunction with bacterial findings? We can only show correlations between findings and clinical entities, yet the majority of findings do seem to correlate well to respiratory tract infections. Therefore, we believe that our conclusion, that significant viral disease in severely ill patients is underdiagnosed by clinicians, is warranted. Diagnosing these infections early may be of help for the clinical decision making process and thereby for the patients.
Seasonality is well described for several viral respiratory pathogens [5, 6]. In our study there was a seasonal predominance for RSV-A from September to December, FluA was more frequent from December to February, FluB from December to April, and HMPV predominated from February to May. In contrast, RV, EV, AdV, and PIV-3 were present during all the study period (Figure 2).