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New and Emerging Infections of the Lung

Identifieur interne : 000782 ( Pmc/Corpus ); précédent : 000781; suivant : 000783

New and Emerging Infections of the Lung

Auteurs : Paul Tambyah ; Mas Suhaila Isa ; Christelle Xian-Ting Tan

Source :

RBID : PMC:7151841

Abstract

In this era of rapid globalization and frequent travel, emerging viral infections have gained an immense potential to spread at an unprecedented speed and scale compared with the past. This poses a significant challenge to coordinated international efforts in global surveillance and infection control.

Significantly, respiratory viral infections, spread mostly via droplet transmission, are extremely contagious and have caused significant morbidity and mortality during outbreaks in the last decade. Molecular diagnostics via reverse transcriptase polymerase chain reaction (RT-PCR) have been key in the rapid diagnosis of most of these viral infections. However, a high index of suspicion and early institution of appropriate isolation measures remain as the mainstay in the control and containment of the spread of these viral infections. Although treatment for most of the viral infections remains supportive, efficacious antiviral agents against influenza infections exist.

The infections discussed in this chapter include those first described in the 2000s: Middle East respiratory syndrome coronavirus (MERS-CoV) and metapneumovirus and rhinovirus C as well as those that have been described in the past but have reemerged in the last decade in outbreaks resulting in significant morbidity and mortality, including adenovirus, influenza virus, and enterovirus D68 (EV-D68).


Url:
DOI: 10.1016/B978-0-323-44887-1.00028-6
PubMed: NONE
PubMed Central: 7151841

Links to Exploration step

PMC:7151841

Le document en format XML

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<name sortKey="Isa, Mas Suhaila" sort="Isa, Mas Suhaila" uniqKey="Isa M" first="Mas Suhaila" last="Isa">Mas Suhaila Isa</name>
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<name sortKey="Tan, Christelle Xian Ting" sort="Tan, Christelle Xian Ting" uniqKey="Tan C" first="Christelle Xian-Ting" last="Tan">Christelle Xian-Ting Tan</name>
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<div type="abstract" xml:lang="en">
<p>In this era of rapid globalization and frequent travel, emerging viral infections have gained an immense potential to spread at an unprecedented speed and scale compared with the past. This poses a significant challenge to coordinated international efforts in global surveillance and infection control.</p>
<p>Significantly, respiratory viral infections, spread mostly via droplet transmission, are extremely contagious and have caused significant morbidity and mortality during outbreaks in the last decade. Molecular diagnostics via reverse transcriptase polymerase chain reaction (RT-PCR) have been key in the rapid diagnosis of most of these viral infections. However, a high index of suspicion and early institution of appropriate isolation measures remain as the mainstay in the control and containment of the spread of these viral infections. Although treatment for most of the viral infections remains supportive, efficacious antiviral agents against influenza infections exist.</p>
<p>The infections discussed in this chapter include those first described in the 2000s: Middle East respiratory syndrome coronavirus (MERS-CoV) and metapneumovirus and rhinovirus C as well as those that have been described in the past but have reemerged in the last decade in outbreaks resulting in significant morbidity and mortality, including adenovirus, influenza virus, and enterovirus D68 (EV-D68).</p>
</div>
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<pmc article-type="chapter-article">
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<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Kendig's Disorders of the Respiratory Tract in Children</journal-id>
<journal-title-group>
<journal-title>Kendig's Disorders of the Respiratory Tract in Children</journal-title>
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</journal-meta>
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<article-id pub-id-type="pmc">7151841</article-id>
<article-id pub-id-type="publisher-id">B978-0-323-44887-1.00028-6</article-id>
<article-id pub-id-type="doi">10.1016/B978-0-323-44887-1.00028-6</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Article</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>New and Emerging Infections of the Lung</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" id="au0010">
<name>
<surname>Tambyah</surname>
<given-names>Paul</given-names>
</name>
<degrees>MD</degrees>
</contrib>
<contrib contrib-type="author" id="au0015">
<name>
<surname>Isa</surname>
<given-names>Mas Suhaila</given-names>
</name>
<degrees>MBBS, MRCPCH (UK)</degrees>
</contrib>
<contrib contrib-type="author" id="au0020">
<name>
<surname>Tan</surname>
<given-names>Christelle Xian-Ting</given-names>
</name>
<degrees>MBBS (S'pore), MRCPCH (UK), MMed (Paeds)</degrees>
</contrib>
</contrib-group>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Wilmott</surname>
<given-names>Robert William</given-names>
</name>
<degrees>BSc, MB, BS, MD, FRCP (UK)</degrees>
</contrib>
</contrib-group>
<aff>IMMUNO Professor and Chair, Department of Pediatrics, Saint Louis University</aff>
<aff>Pediatrician in Chief, SSM Cardinal Glennon Children's Medical Center, St. Louis, Missouri, United States</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Deterding</surname>
<given-names>Robin</given-names>
</name>
<degrees>MD</degrees>
</contrib>
</contrib-group>
<aff>Chief, Pediatric Pulmonary Medicine, Professor of Pediatrics, Department of Pediatrics, University of Colorado, Aurora, Colorado, United States</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Li</surname>
<given-names>Albert</given-names>
</name>
<degrees>MBBch, MD, MRCPCH, MRCP(UK), FHKAM(Paeds), FHKCPaed</degrees>
</contrib>
</contrib-group>
<aff>Assistant Dean (Education), Faculty of Medicine, Professor of Paediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Ratjen</surname>
<given-names>Felix</given-names>
</name>
<degrees>MD, PhD, FRCP(C), FERS</degrees>
</contrib>
</contrib-group>
<aff>Head, Division of Respiratory Medicine</aff>
<aff>Program Head, Translational Medicine, Sellers Chair of Cystic Fibrosis</aff>
<aff>Professor, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Sly</surname>
<given-names>Peter</given-names>
</name>
<degrees>MBBS, MD, FRACP, DSc</degrees>
</contrib>
</contrib-group>
<aff>Director, Children's Lung Environment and Asthma Research Group, University of Queensland, Brisbane, Australia</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Zar</surname>
<given-names>Heather J.</given-names>
</name>
<degrees>MBBCh, FCPaeds, FRCP (Edinburgh), PhD</degrees>
</contrib>
</contrib-group>
<aff>Professor and Chair, Department of Paediatrics & Child Health</aff>
<aff>Director MRC Unit on Child & Adolescent Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>Bush</surname>
<given-names>Andrew</given-names>
</name>
<degrees>MB BS(Hons), MA, MD, FRCP, FRCPCH, FERS</degrees>
</contrib>
</contrib-group>
<aff>Professor of Paediatrics and Head of Section, Imperial College London</aff>
<aff>Professor of Paediatric Respirology, National Heart and Lung Institute</aff>
<aff>Consultant Paediatric Chest Physician, Royal Brompton Harefield NHS Foundation Trust, London, Great Britain</aff>
<pub-date pub-type="pmc-release">
<day>13</day>
<month>3</month>
<year>2018</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="ppub">
<year>2019</year>
</pub-date>
<pub-date pub-type="epub">
<day>13</day>
<month>3</month>
<year>2018</year>
</pub-date>
<fpage>466</fpage>
<lpage>474.e2</lpage>
<permissions>
<copyright-statement>Copyright © 2019 Elsevier Inc. All rights reserved.</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Elsevier Inc.</copyright-holder>
<license>
<license-p>Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.</license-p>
</license>
</permissions>
<abstract id="ab0010">
<p>In this era of rapid globalization and frequent travel, emerging viral infections have gained an immense potential to spread at an unprecedented speed and scale compared with the past. This poses a significant challenge to coordinated international efforts in global surveillance and infection control.</p>
<p>Significantly, respiratory viral infections, spread mostly via droplet transmission, are extremely contagious and have caused significant morbidity and mortality during outbreaks in the last decade. Molecular diagnostics via reverse transcriptase polymerase chain reaction (RT-PCR) have been key in the rapid diagnosis of most of these viral infections. However, a high index of suspicion and early institution of appropriate isolation measures remain as the mainstay in the control and containment of the spread of these viral infections. Although treatment for most of the viral infections remains supportive, efficacious antiviral agents against influenza infections exist.</p>
<p>The infections discussed in this chapter include those first described in the 2000s: Middle East respiratory syndrome coronavirus (MERS-CoV) and metapneumovirus and rhinovirus C as well as those that have been described in the past but have reemerged in the last decade in outbreaks resulting in significant morbidity and mortality, including adenovirus, influenza virus, and enterovirus D68 (EV-D68).</p>
</abstract>
<kwd-group id="kwd0010">
<title>Keywords</title>
<kwd>emerging infections</kwd>
<kwd>virus</kwd>
<kwd>respiratory</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<sec id="s0010">
<title>Introduction</title>
<p id="p9000">In this era of rapid globalization and frequent travel, emerging viral infections have gained an immense potential to spread at an unprecedented speed and scale compared with the past. This poses a significant challenge to coordinated international efforts in global surveillance and infection control.</p>
<p id="p9005">Significantly, respiratory viral infections, spread mostly via droplet transmission, are extremely contagious and have caused significant morbidity and mortality during outbreaks in the last decade. Molecular diagnostics via reverse transcriptase polymerase chain reaction (RT-PCR) have been key in the rapid diagnosis of most of these viral infections. However, a high index of suspicion and early institution of appropriate isolation measures remain as the mainstay in the control and containment of the spread of these viral infections. Although treatment for most of the viral infections remains supportive, efficacious antiviral agents against influenza infections exist.</p>
<p id="p9010">The infections discussed in this chapter include those first described in the 2000s: Middle East respiratory syndrome coronavirus (MERS-CoV) and metapneumovirus and rhinovirus C as well as those that have been described in the past but have reemerged in the last decade in outbreaks resulting in significant morbidity and mortality, including adenovirus, influenza virus, and enterovirus D68 (EV-D68).</p>
<sec id="s0015">
<title>Epidemiology</title>
<p id="p0025">EV-D68 was first isolated in 1962 in California and had been rare with occasional reports of clusters. Since the late 2000s, EV-D68 has been increasingly reported in various parts of the world. In August 2014, the US Centers for Disease Control and Prevention (CDC) reported cases beginning in the Midwest, with more than 1000 cases reported in 49 states in 2014.
<xref rid="bib1" ref-type="bibr">
<sup>1</sup>
</xref>
</p>
</sec>
<sec id="s0020">
<title>Etiology</title>
<p id="p0030">EV-D68 is a single-stranded, nonenveloped RNA virus. It belongs to the genus
<italic>Enteroviruses</italic>
and family Picornaviridae. It is one of the five EV-D serotypes identified so far. It has virologic characteristics including the ability to bind to α-2, 6-linked sialic acids that are present in the upper respiratory tract, which facilitate respiratory infections (
<xref rid="t0010" ref-type="table">Table 28.1</xref>
).
<xref rid="bib2" ref-type="bibr">
<sup>2</sup>
</xref>
<table-wrap position="float" id="t0010">
<label>Table 28.1</label>
<caption>
<p>Summary Table of Characteristics of Emerging Viral Respiratory Infections</p>
</caption>
<alt-text id="atte0025">Table 28.1</alt-text>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left">Virus</th>
<th align="left">Mode of Transmission</th>
<th align="left">Incubation Period</th>
<th align="left">Clinical Features</th>
<th align="left">Diagnosis
<xref rid="tn0010" ref-type="table-fn">a</xref>
</th>
<th align="left">Management and Treatment</th>
<th align="left">Prophylaxis</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left">Enterovirus D68 (EV-D68)</td>
<td align="left">
<list list-type="simple" id="ulist0010">
<list-item id="u0010">
<label>▪</label>
<p id="p0035">Droplet</p>
</list-item>
<list-item id="u0015">
<label>▪</label>
<p id="p0040">Fecal-oral</p>
</list-item>
<list-item id="u0020">
<label>▪</label>
<p id="p0045">Fomites</p>
</list-item>
</list>
</td>
<td align="left">1–5 days</td>
<td align="left">
<list list-type="simple" id="ulist0015">
<list-item id="u0025">
<label>▪</label>
<p id="p0050">Respiratory</p>
</list-item>
<list-item id="u0030">
<label>▪</label>
<p id="p0055">Rarely flaccid myelitis</p>
</list-item>
<list-item id="u0035">
<label>▪</label>
<p id="p0060">Predilection to atopic individuals</p>
</list-item>
</list>
</td>
<td align="left">
<list list-type="simple" id="ulist0020">
<list-item id="u0040">
<label>▪</label>
<p id="p0065">PCR</p>
</list-item>
<list-item id="u0045">
<label>▪</label>
<p id="p0070">Viral cultures</p>
</list-item>
<list-item id="u0050">
<label>▪</label>
<p id="p0075">(including serum)</p>
</list-item>
</list>
</td>
<td align="left">Supportive</td>
<td align="left"></td>
</tr>
<tr>
<td align="left">MERS-CoV</td>
<td align="left">
<list list-type="simple" id="ulist0025">
<list-item id="u0055">
<label>▪</label>
<p id="p0080">Droplet</p>
</list-item>
</list>
</td>
<td align="left">2–14 days, median of 5 days</td>
<td align="left">
<list list-type="simple" id="ulist0030">
<list-item id="u0060">
<label>▪</label>
<p id="p0085">ARDS</p>
</list-item>
<list-item id="u0065">
<label>▪</label>
<p id="p0090">Myalgia</p>
</list-item>
<list-item id="u0070">
<label>▪</label>
<p id="p0095">Gastrointestinal</p>
</list-item>
<list-item id="u0075">
<label>▪</label>
<p id="p0100">Asymptomatic</p>
</list-item>
</list>
</td>
<td align="left">
<list list-type="simple" id="ulist0035">
<list-item id="u0080">
<label>▪</label>
<p id="p0105">RT-PCR (including stool specimens)</p>
</list-item>
</list>
</td>
<td align="left">Supportive</td>
<td align="left"></td>
</tr>
<tr>
<td align="left">Human metapneumovirus</td>
<td align="left">
<list list-type="simple" id="ulist0040">
<list-item id="u0085">
<label>▪</label>
<p id="p0110">Droplet</p>
</list-item>
<list-item id="u0090">
<label>▪</label>
<p id="p0115">Fomites</p>
</list-item>
</list>
</td>
<td align="left">4–6 days
<break></break>
Shedding can last 1–2 weeks</td>
<td align="left">
<list list-type="simple" id="ulist0045">
<list-item id="u0095">
<label>▪</label>
<p id="p0120">Respiratory</p>
</list-item>
<list-item id="u0100">
<label>▪</label>
<p id="p0125">Gastrointestinal</p>
</list-item>
<list-item id="u0105">
<label>▪</label>
<p id="p0130">Predisposes to severe bacterial infections</p>
</list-item>
</list>
</td>
<td align="left">
<list list-type="simple" id="ulist0050">
<list-item id="u0110">
<label>▪</label>
<p id="p0135">RT-PCR</p>
</list-item>
<list-item id="u0115">
<label>▪</label>
<p id="p0140">Immunofluorescence assay (IFA)</p>
</list-item>
</list>
</td>
<td align="left">Supportive
<break></break>
Intravenous immunoglobulin
<break></break>
Ribavirin
<break></break>
Investigational therapies</td>
<td align="left"></td>
</tr>
<tr>
<td align="left">Rhinovirus C</td>
<td align="left">
<list list-type="simple" id="ulist0055">
<list-item id="u0120">
<label>▪</label>
<p id="p0145">Aerosol or droplet</p>
</list-item>
<list-item id="u0125">
<label>▪</label>
<p id="p0150">Fomites</p>
</list-item>
</list>
</td>
<td align="left">0.5–3 days</td>
<td align="left">
<list list-type="simple" id="ulist0060">
<list-item id="u0130">
<label>▪</label>
<p id="p0155">Respiratory</p>
</list-item>
<list-item id="u0135">
<label>▪</label>
<p id="p0160">Coinfection with bacterial infections common</p>
</list-item>
</list>
</td>
<td align="left">
<list list-type="simple" id="ulist0065">
<list-item id="u0140">
<label>▪</label>
<p id="p0165">RT-PCR</p>
</list-item>
</list>
</td>
<td align="left">Supportive</td>
<td align="left"></td>
</tr>
<tr>
<td align="left">Adenovirus</td>
<td align="left">
<list list-type="simple" id="ulist0070">
<list-item id="u0145">
<label>▪</label>
<p id="p0170">Aerosol or droplet</p>
</list-item>
<list-item id="u0150">
<label>▪</label>
<p id="p0175">Fomites</p>
</list-item>
<list-item id="u0155">
<label>▪</label>
<p id="p0180">Fecal-oral</p>
</list-item>
</list>
</td>
<td align="left">2–14 days
<break></break>
Shedding up to 2 years in stool</td>
<td align="left">
<list list-type="simple" id="ulist0075">
<list-item id="u0160">
<label>▪</label>
<p id="p0185">Pharyngoconjunctival fever</p>
</list-item>
<list-item id="u0165">
<label>▪</label>
<p id="p0190">Respiratory</p>
</list-item>
<list-item id="u0170">
<label>▪</label>
<p id="p0195">Gastrointestinal</p>
</list-item>
<list-item id="u0175">
<label>▪</label>
<p id="p0200">Renal-hematuria</p>
</list-item>
</list>
</td>
<td align="left">
<list list-type="simple" id="ulist0080">
<list-item id="u0180">
<label>▪</label>
<p id="p0205">DFA</p>
</list-item>
<list-item id="u0185">
<label>▪</label>
<p id="p0210">PCR (throat, sputum and rectal swabs; blood and stool in immunocompromised)</p>
</list-item>
<list-item id="u0190">
<label>▪</label>
<p id="p0215">Serologic rise in antibody titers</p>
</list-item>
</list>
</td>
<td align="left">Supportive
<break></break>
Cidofovir for severe infections
<xref rid="tn0015" ref-type="table-fn">b</xref>
</td>
<td align="left">Oral vaccine (types 4 and 7)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn>
<p>
<italic>ARDS,</italic>
Acute respiratory distress syndrome;
<italic>ARF,</italic>
acute renal failure;
<italic>DFA,</italic>
direct fluorescent assay;
<italic>MERS-CoV,</italic>
Middle East respiratory syndrome coronavirus;
<italic>RT-PCR,</italic>
reverse transcriptase polymerase chain reaction.</p>
</fn>
</table-wrap-foot>
<table-wrap-foot>
<fn id="tn0010">
<label>a</label>
<p id="np0010">Unless otherwise stated, samples were obtained from the nasopharynx or oropharynx.</p>
</fn>
</table-wrap-foot>
<table-wrap-foot>
<fn id="tn0015">
<label>b</label>
<p id="np0015">Off-label use.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</p>
</sec>
<sec id="s0025">
<title>Pathology/Pathogenesis</title>
<p id="p0220">The pathogenesis of EV-D68 has been studied in animal models. Schieble and colleagues noted that the Rhyne strain demonstrated a neurotropic virulence with paralysis of mice. However, despite the predominant respiratory symptoms seen in humans, no effective animal models have been established. Humans are at the moment the only known natural reservoirs of the disease.</p>
</sec>
<sec id="s0030">
<title>Clinical Features</title>
<p id="p0225">The incubation period for EV-D68 is between 1–5 days, similar to many other viral respiratory infections, and the infectious period lasts from a day prior to symptom onset to about 5 days after onset. Spread of infection occurs by droplet transmission and through the fecal-oral route or indirect contact with contaminated surfaces, as with other enteroviruses.</p>
</sec>
<sec id="s0035">
<title>Symptoms</title>
<p id="p0230">EV-D68 primarily causes acute respiratory symptoms, unlike other enteroviruses. Presenting symptoms range from mild upper respiratory symptoms such as rhinorrhea, sore throat, fever, and rash to severe pneumonia. Most reported cases were associated with difficulty breathing and wheezing, but this may affected by reporting bias.
<xref rid="bib3" ref-type="bibr">
<sup>3</sup>
</xref>
</p>
<p id="p0235">Patients can also present with aseptic meningitis or encephalitis. EV-D68 infection has been reported to have a predilection for patients with a personal or family history of atopy.
<xref rid="bib1" ref-type="bibr">
<sup>1</sup>
</xref>
The respiratory symptoms have also been reported to be more severe in those with underlying respiratory illnesses such as asthma, often requiring intensive care treatment. Prior to virological diagnosis, many of these cases were often discharged with a diagnosis of asthma exacerbation.</p>
<p id="p0240">During the outbreak in California and Colorado, a significant group of children was reported to have presented with acute flaccid myelitis, symptoms of sudden asymmetric limb weakness, facial weakness, ophthalmoplegia, or bulbar signs; they were found to be positive for EV-D68 in their nasopharyngeal swabs. However, the spectrum of neurologic disease associated with EV-D68 has not been fully characterized.</p>
</sec>
<sec id="s0040">
<title>Physical Findings</title>
<p id="p0245">The physical findings for infected patients are similar to those associated with most respiratory viral infections and are not specific to the disease. However, a significant number of EV-D68 patients have been reported with wheezing as the main clinical feature. Patients with more severe EV-D68 respiratory infections present with tachypnea and retractions.
<xref rid="bib3" ref-type="bibr">
<sup>3</sup>
</xref>
As already mentioned, neurologic symptoms including flaccid myelitis have also been associated with EV-D68 infections.</p>
</sec>
<sec id="s0045">
<title>Imaging, Pulmonary Function Tests, Laboratory Findings</title>
<p id="p0250">Chest radiographs often demonstrate peribronchial thickening and infiltrates, often with areas of atelectasis.
<xref rid="bib4" ref-type="bibr">4</xref>
,
<xref rid="bib5" ref-type="bibr">5</xref>
</p>
</sec>
<sec id="s0050">
<title>Diagnosis and Differential Diagnosis</title>
<p id="p0255">EV-D68 can be identified using molecular methods, polymerase chain reaction (PCR), or viral cultures of fluid samples from the nasopharynx, oropharynx, and serum. Most commercially available respiratory multiplex PCR assays may not be able to distinguish enteroviruses from rhinoviruses, so specific assays for EV-D68 may be needed to identify infections with EV-D68 if the clinical suspicion is high.</p>
</sec>
<sec id="s0055">
<title>Management and Treatment</title>
<p id="p0260">Supportive care remains the mainstay of treatment. No specific treatment is currently available.
<xref rid="bib4" ref-type="bibr">
<sup>4</sup>
</xref>
Pleconaril has not been shown to be effective for EV-D68 to date.</p>
</sec>
<sec id="s0060">
<title>Prevention</title>
<p id="p0265">There are currently no available vaccines. Good hand hygiene and prompt diagnosis with subsequent isolation of cases is the main approach to containing the spread of these infections.</p>
</sec>
<sec id="s0065">
<title>Prognosis</title>
<p id="p0270">Initial studies had suggested that patients with EV-D68 infection, compared with other pulmonary pathogens such as rhinoviruses or non EV-D68 enteroviruses, were more likely to have severe respiratory symptoms and to require hospitalization.
<xref rid="bib1" ref-type="bibr">
<sup>1</sup>
</xref>
However, in a more recent retrospective analysis of the outbreak at the St. Louis Children's Hospital,
<xref rid="bib3" ref-type="bibr">
<sup>3</sup>
</xref>
the cases analyzed have shown no significant difference in severity of illness in EV-D68 patients compared with those with other viral etiologies. This may have been due to ascertainment bias, as more severely affected children were tested and thus the case fatality rate appeared to be much higher than it probably really was. This has happened with a number of respiratory viruses, including influenza A H1N1 in 2009, when it was first recognized.</p>
<p id="p0275">In most cases of EV-D68 infection, with supportive care recovery is expected over a few days. Fatalities have been associated with neurologic complications or occasionally cardiac events.
<xref rid="bib6" ref-type="bibr">6</xref>
,
<xref rid="bib7" ref-type="bibr">7</xref>
</p>
</sec>
</sec>
<sec id="s0070">
<title>Middle East Respiratory Syndrome Coronavirus</title>
<sec id="s0075">
<title>Epidemiology</title>
<p id="p0280">First reported in April 2012 in Jordan,
<xref rid="bib8" ref-type="bibr">
<sup>8</sup>
</xref>
MERS-CoV spread rapidly to the Middle East, including the Kingdom of Saudi Arabia (KSA), the United Arab Emirates (UAE), and Qatar. Subsequent imported cases were then reported in European countries including France, the United Kingdom, Italy, and Germany and in North Africa (Tunisia). After the 2012 outbreak, there were only sporadic cases and nosocomial outbreaks reported from the Middle East until 2015, when a large outbreak occurred in Korea and Guangdong (China) involving 184 cases and 33 deaths.
<xref rid="bib9" ref-type="bibr">
<sup>9</sup>
</xref>
Since 2012, according to statistics from the World Health Organization (WHO), there have been 1365 laboratory-confirmed cases of MERS-CoV infection, including 487 related deaths.</p>
</sec>
<sec id="s0080">
<title>Etiology</title>
<p id="p0285">MERS-CoV is an enveloped single-stranded RNA virus belonging to the family Coronaviridae. As with most coronaviruses, the reservoir of infection is thought to originate from animals. MERS-CoV is postulated to have originated from the dromedary camels within the Arabian Peninsula. Molecular isolation of several alphacoronaviruses and betacoronaviruses from bats in Saudi Arabia and other parts of the world has suggested the involvement of bats in human infection as well. The actual route of zoonotic transmission has not been clearly defined despite the publication of a large case-control study.
<xref rid="bib10" ref-type="bibr">
<sup>10</sup>
</xref>
</p>
</sec>
<sec id="s0085">
<title>Pathology/Pathogenesis</title>
<p id="p0290">The exact pathogenesis of MERS-CoV is being elucidated. Studies looking at ex vivo infected hepatoma cells demonstrate severe cytopathic effects.
<xref rid="bib11" ref-type="bibr">
<sup>11</sup>
</xref>
Hocke and colleagues
<xref rid="bib12" ref-type="bibr">
<sup>12</sup>
</xref>
have demonstrated, through spectral microscopy, significant MERS-CoV antigen expression in type I and II alveolar cells, ciliated bronchial epithelium, and unciliated cuboidal cells of terminal bronchioles as well as pulmonary vessel endothelial cells. Evidence of alveolar epithelial damage with detachment of type II alveolar epithelial cells and associated disruption of tight junctions, chromatin condensation, nuclear fragmentation, and membrane blebbing were seen on electron microscopy.
<xref rid="bib12" ref-type="bibr">
<sup>12</sup>
</xref>
The receptor for MERS-CoV has been identified as dipeptidyl peptidase 4 (DPP4) (CD26), an exopeptidase, which has been demonstrated in cells on spectral microscopy.
<xref rid="bib11" ref-type="bibr">
<sup>11</sup>
</xref>
</p>
<p id="p0295">MERS-CoV infection causes significant host immune dysregulation with downregulation of genes involved in the antigen-presenting pathway, leading to subsequent impaired adaptive immune responses, possibly explaining the rapid progression of the illness and the high mortality rate.</p>
</sec>
<sec id="s0090">
<title>Clinical Features</title>
<p id="p0300">Most of the MERS-CoV infections were spread via travel to or residence in countries near the Arabian Peninsula. Infection occurs via droplet transmission from patients to close contacts. The risk of person-to-person transmission is generally low, but superspreading events have been identified similar to the severe acute respiratory syndrome (SARS) coronavirus, in which single individuals have been associated with transmission to large numbers of others. The median incubation period for secondary cases of human-to-human transmission is about 5 days (range 2–14 days).
<xref rid="bib13" ref-type="bibr">
<sup>13</sup>
</xref>
</p>
</sec>
<sec id="s0095">
<title>Symptoms</title>
<p id="p0305">In adults, infection results in fever as well as upper and lower respiratory tract symptoms including cough and breathlessness, which can rapidly deteriorate to severe acute respiratory distress syndrome. Other symptoms of myalgia and gastrointestinal symptoms of diarrhea, vomiting, and abdominal pain were commonly present.
<xref rid="bib14" ref-type="bibr">
<sup>14</sup>
</xref>
However, two case series from the Middle East
<xref rid="bib15" ref-type="bibr">15</xref>
,
<xref rid="bib16" ref-type="bibr">16</xref>
have reported that MERS-CoV infection ran a milder course in children, with the majority being asymptomatic carriers who were contacts of symptomatic adult cases. Severe respiratory symptoms occurred more commonly in those with existing comorbidities.</p>
<p id="p0310">The reported patients' age range has been from below 1 year to 99 years of age, although children have formed a minority of cases. This may be due to limited exposure to animals or health care settings where most infections have occurred.</p>
<p id="p0315">The respiratory symptoms in symptomatic cases are rapidly progressive, with the median time from onset of symptoms to hospitalization being about 4 days and from onset to intensive care admission for severe cases approximately 5 days. Complications include acute respiratory failure, acute respiratory distress syndrome, refractory hypoxemia, and extrapulmonary complications (ischemic hepatitis, septic shock, hypotension, acute renal failure). The median time from onset to death was about 12 days.
<xref rid="bib13" ref-type="bibr">
<sup>13</sup>
</xref>
</p>
</sec>
<sec id="s0100">
<title>Physical Findings</title>
<p id="p0320">Patients presenting with symptomatic MERS-CoV infection have mainly lower respiratory findings, including tachypnea, rhonchi, and retractions, although upper respiratory symptoms have been reported.</p>
</sec>
<sec id="s0105">
<title>Imaging, Pulmonary Function Tests, Laboratory Findings</title>
<p id="p0325">Reported chest x-ray findings have included unilateral or bilateral patchy opacities, consolidation, interstitial infiltrates, and pleural effusions.
<xref rid="bib13" ref-type="bibr">
<sup>13</sup>
</xref>
</p>
</sec>
<sec id="s0110">
<title>Diagnosis and Differential Diagnosis</title>
<p id="p0330">Laboratory confirmation of active MERS-coV infection is based on real-time reverse transcription PCR (RT-PCR) detection of at least two specific genomic targets or a single positive target with sequencing of a second target.
<xref rid="bib17" ref-type="bibr">
<sup>17</sup>
</xref>
Confirmation with nucleic acid sequencing may be required for epidemiologic investigation of the origin and spread of the disease. Specimen collection sites for RT-PCR include lower respiratory samples (bronchoalveolar lavage, tracheal, or sputum aspirates) and upper respiratory samples (nasopharyngeal and oropharyngeal swabs) as well as serum and stool specimens, although the highest yield has been from respiratory samples.
<xref rid="bib17" ref-type="bibr">
<sup>17</sup>
</xref>
</p>
<p id="p0335">Serologic testing by enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA) or microneutralization assay is available for the detection of previous infection and is used mainly for surveillance purposes; it should not be used as a diagnostic tool as there is a risk of cross-reactivity with other coronaviruses.</p>
<p id="p0340">A single negative result on a recommended specimen sent is sufficient to demonstrate no active MERS-CoV infection according to the definition of the US CDC. However, if the clinical suspicion remains, more samples should be sent, as false-negatives do occur.</p>
<p id="p0345">Patients who have been diagnosed with MERS-CoV are considered clear of active infection and can be deisolated when two consecutive specimen tests are negative on RT-PCR.</p>
<p id="p0350">Other infectious etiologies presenting similarly with acute, rapidly progressive respiratory distress syndrome include SARS and influenza virus (H5N1). Noninfective causes of acute respiratory distress syndrome (ARDS) should be considered as well. The epidemiologic history and a high index of clinical suspicion are critical.</p>
</sec>
<sec id="s0115">
<title>Management and Treatment</title>
<p id="p0355">No specific antivirals have developed at this point, and the mainstay of treatment remains supportive care.</p>
</sec>
<sec id="s0120">
<title>Prevention</title>
<p id="p0360">Currently no vaccine is available against MERS-CoV. Strict infection control measures, including standard, contact, and droplet precautions, with airborne precautions for aerosol-generating procedures, must be taken when care is being provided for suspected or confirmed cases. These have been shown to be effective in controlling nosocomial outbreaks in both the KSA and South Korea. Continued vigilant epidemiologic surveillance, good hand hygiene, and cough etiquette remain the mainstays of prevention for areas not affected by outbreaks.</p>
</sec>
<sec id="s0125">
<title>Prognosis</title>
<p id="p0365">The prognosis is guarded in symptomatic cases, especially in adults, with 3–4 of every 10 patients reported to have died. The number of children infected has been small, so it remains to be seen if the disease runs a more benign course in the pediatric age group. In the adult population, patients admitted to the intensive care unit had a 58% mortality rate at 90 days post admission.
<xref rid="bib18" ref-type="bibr">
<sup>18</sup>
</xref>
</p>
</sec>
</sec>
<sec id="s0130">
<title>Human Metapneumovirus</title>
<sec id="s0135">
<title>Epidemiology</title>
<p id="p0370">Human metapneumovirus (HMPV) was first isolated in pediatric patients with acute respiratory infections in the Netherlands in 2001.
<xref rid="bib19" ref-type="bibr">
<sup>19</sup>
</xref>
Subsequent retrospective serologic studies demonstrated the presence of antibodies to HMPV in humans more than 50 years prior,
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
and the virus has since been found worldwide. HMPV accounts for up to 10% of viral respiratory tract infections, occurring commonly during the months of January through April in the United States.
<xref rid="bib21" ref-type="bibr">
<sup>21</sup>
</xref>
However, a recent 7-year surveillance study in the United States reported that the HMPV season occurred after the respiratory syncytial virus (RSV) and influenza seasons.
<xref rid="bib22" ref-type="bibr">
<sup>22</sup>
</xref>
Serologic studies have demonstrated that most children in Europe and North America have acquired a HMPV infection at least once by the age of 5 years.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
Although this is a common childhood respiratory infection, immunity is believed to be transient, and HMPV infection is reported to contribute to acute respiratory illnesses in the elderly (above age 65) who have comorbid respiratory conditions such as asthma or chronic obstructive pulmonary disease or conditions resulting in an immunocompromised status. The overall rate of detection of HMPV was 6% among hospitalized children with respiratory studies.
<xref rid="bib21" ref-type="bibr">
<sup>21</sup>
</xref>
Although there have been questions as to whether HMPV is truly a pathogen, asymptomatic carriage among children is estimated to be only 1%.
<xref rid="bib21" ref-type="bibr">
<sup>21</sup>
</xref>
</p>
</sec>
<sec id="s0140">
<title>Etiology</title>
<p id="p0375">HMPV is an enveloped single-stranded RNA virus and is a member of the Paramyxoviridae family, belonging to the subfamily Pneumovirinae under the genus
<italic>Metapneumovirus.</italic>
Two genotypes of HMPV exist, A and B; subgroups are based on the fusion (F) and attachment (G) surface glycoproteins.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
</p>
</sec>
<sec id="s0145">
<title>Pathology/Pathogenesis</title>
<p id="p0380">The pathogenesis of HMPV infection has been extensively studied in multiple animal models. Studies on young adult cotton rats inoculated with the virus demonstrate inflammation within and surrounding the bronchi and bronchioles with significant leukocytosis. The HMPV was found mostly on the apical surface of the columnar cells. In the same animal model, upregulation of mRNAs related to interferon gamma (IFN)-α, CCL5, CCL2, CCL3 and interleukin (IL)-2 was demonstrated. Previous infection conferred partial protection in these rats, with lower viral loads within the respiratory tract and a neutralizing antibody response on subsequent infection.
<xref rid="bib23" ref-type="bibr">
<sup>23</sup>
</xref>
However, long-term immunity seems unlikely given the incidence of disease in older adults.</p>
</sec>
<sec id="s0150">
<title>Clinical Features</title>
<p id="p0385">HMPV infection is transmitted via close or direct contact with contaminated secretions; the incubation period of HMPV is estimated to be 4–6 days.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
The duration of symptoms varies according to severity, but it is commonly less than a week. However, shedding of the virus in infected cases can last from 1 to 2 weeks after the acute illness, with viral RNA found in stools 5 days to 2 weeks after symptom initiation.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
A large prospective surveillance study done by the US CDC on HMPV infection in children
<xref rid="bib21" ref-type="bibr">
<sup>21</sup>
</xref>
found that infected children were mostly without comorbidities and most were younger than 5 years of age, with many infants less than 6 months of age. The annual rate of hospitalization associated with HPMV infection was similar to that of influenza virus (1 per 1000) but lower than that for RSV (3 per 1000).
<xref rid="bib19" ref-type="bibr">
<sup>19</sup>
</xref>
</p>
</sec>
<sec id="s0155">
<title>Symptoms</title>
<p id="p0390">Clinical infection with HMPV results in initial upper respiratory tract symptoms such as cough, rhinorrhea, and fever and can progress to lower respiratory tract symptoms of shortness of breath and wheezing. Sore throat, conjunctivitis, poor appetite, rash, and other gastrointestinal symptoms such as vomiting and diarrhea have been reported.
<xref rid="bib23" ref-type="bibr">23</xref>
,
<xref rid="bib24" ref-type="bibr">24</xref>
,
<xref rid="bib25" ref-type="bibr">25</xref>
The diagnosis is often not made clinically. In a 2-year population-based prospective surveillance study, outpatient cases subsequently found to be positive for HMPV were discharged mostly with the diagnosis of viral illness and bronchiolitis, while inpatient cases were mostly discharged with a diagnosis of bronchiolitis, asthma, or pneumonia.
<xref rid="bib25" ref-type="bibr">
<sup>25</sup>
</xref>
Although infections are usually mild and self-limiting, some studies suggest that HMPV infections can predispose to severe bacterial infections, which complicate the course of the disease.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
</p>
</sec>
<sec id="s0160">
<title>Physical Findings</title>
<p id="p0395">Clinical findings in infected cases are like those seen in other respiratory viral infections, although fever was less common in children with HMPV infections than those with influenza in one study.
<xref rid="bib25" ref-type="bibr">
<sup>25</sup>
</xref>
However, findings of respiratory distress, tachypnea, and wheezing were more common in patients with HMPV infections than in those with influenza in the same study.</p>
</sec>
<sec id="s0165">
<title>Imaging, Pulmonary Function Tests, Laboratory Findings</title>
<p id="p0400">Initial laboratory findings may reveal lymphopenia, neutropenia, and transaminitis,
<xref rid="bib26" ref-type="bibr">
<sup>26</sup>
</xref>
or they may be completely normal. Chest x-ray findings for lower respiratory tract involvement in severe disease, especially in the immunocompromised, have demonstrated ground-glass opacities with parenchymal airspace consolidation, ill-defined nodular-like centrilobular opacities and bronchial wall thickening (
<xref rid="f0010" ref-type="fig">Fig. 28.1</xref>
).
<xref rid="bib26" ref-type="bibr">
<sup>26</sup>
</xref>
Compared with RSV pneumonia, in one series HMPV pneumonia showed more asymmetrical findings.
<xref rid="bib26" ref-type="bibr">
<sup>26</sup>
</xref>
<fig id="f0010">
<label>Fig. 28.1</label>
<caption>
<p>Chest x-ray in a 4-year-old patient with underlying acute lymphoblastic leukemia demonstrating left mid- to lower-zone consolidation consistent with a left-sided pneumonia. The bronchoalveolar lavage fluid was positive for human metapneumovirus on reverse transcriptase polymerase chain reaction testing.</p>
</caption>
<alt-text id="atte0010">Fig. 28.1</alt-text>
<graphic xlink:href="f028-001-9780323448871"></graphic>
</fig>
</p>
</sec>
<sec id="s0170">
<title>Diagnosis and Differential Diagnosis</title>
<p id="p0405">Diagnostic tests for HMPV infection include various techniques of culture, the nucleic acid amplification test (NAAR), antigen detection and serologic testing. As culturing the virus is technically challenging owing to its slow growth and cytopathic effects in vitro, the most commonly used detection technique is via RT-PCR from nasopharyngeal or oropharyngeal samples. Direct IFA testing can be done in outbreak settings because of the shorter turnaround time, but IFA has a lower sensitivity.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
Serologic testing has been used mainly for epidemiologic purposes.</p>
<p id="p0410">Differential diagnoses for similar upper respiratory tract presentations would include other viral etiologies including RSV, influenza, parainfluenza, and adenovirus. In the immunocompromised host with lower respiratory tract signs, fungal etiologies would have to be considered as well.</p>
</sec>
<sec id="s0175">
<title>Management and Treatment</title>
<p id="p0415">Treatment of HMPV infections, like that of other viral infections, is mainly supportive; however, there is much interest in developing therapeutic options. Ribavirin, a nucleoside inhibitor licensed for the treatment of RSV and hepatitis C infections, has demonstrated good in vitro and in vivo activity against HMPV in animal models. Antiviral fusion inhibitors are also currently being investigated.</p>
<p id="p0420">Other promising treatment options include therapeutic antibodies. Following the successful introduction of monoclonal antibodies such as palivizumab for RSV infections, development of specific monoclonal antibodies against HMPV is ongoing. An example is MAb338, an antibody targeting the HMPV fusion protein, which has shown therapeutic potential in mouse models. Another example is the intranasally administered Human Fab DS7.
<xref rid="bib27" ref-type="bibr">
<sup>27</sup>
</xref>
Standard intravenous immunoglobulin preparations have also been shown to inhibit replication of HMPV in vitro.
<xref rid="bib28" ref-type="bibr">
<sup>28</sup>
</xref>
</p>
<p id="p0425">RNA interference is a new approach to treating RNA viral infections by regulating gene expression through the silencing of specific mRNAs.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
Two extremely efficient small interfering RNAs against HMPV have been identified by Deffrasnes and colleagues,
<xref rid="bib29" ref-type="bibr">
<sup>29</sup>
</xref>
These are still in the investigation phase. Finally, Wyde and colleagues have investigated the antiviral properties of sulfated sialyl lipid and heparin and have found activity against HMPV in vitro.
<xref rid="bib30" ref-type="bibr">
<sup>30</sup>
</xref>
</p>
<p id="p0430">Although there has yet to be a randomized controlled trial on therapeutics in HMPV infections, in severe case, in uncontrolled studies a combination of oral and aerosolized ribavirin with polyclonal intravenous immunoglobulin had some effect.
<xref rid="bib20" ref-type="bibr">
<sup>20</sup>
</xref>
</p>
</sec>
<sec id="s0180">
<title>Prevention</title>
<p id="p0435">An effective vaccine against HMPV remains to be developed. Strategic targeting of the F and G surface proteins for both live attenuated and inactivated vaccine development is in progress. Particularly challenging is the fact that natural infection confers only transient immunity and reinfections are common into adulthood. This raises questions about the protective effect of any future vaccine.</p>
<p id="p0440">Infection control remains the mainstay of prevention, especially within the hospital. Droplet isolation of infected cases with lower respiratory tract symptoms should be implemented until symptom recovery.</p>
</sec>
<sec id="s0185">
<title>Prognosis</title>
<p id="p0445">Although children infected with HMPV had a higher likelihood of supplemental oxygen use and were noted to have a longer intensive care unit (ICU) stay compared to respiratory infections from other causes, the rates of ICU admission and intubation remained similar to other respiratory infections. The lengths of stay in hospital were not significantly different
<xref rid="bib21" ref-type="bibr">
<sup>21</sup>
</xref>
and fatal HMPV infections are rare.</p>
</sec>
</sec>
<sec id="s0190">
<title>Rhinovirus C</title>
<sec id="s0195">
<title>Epidemiology</title>
<p id="p0450">Human Rhinovirus C (HRV-C) is the newest member of the HRV family, having been discovered only in 2006 after retrospective VP4 sequence analysis, done with respiratory samples from patients in Queensland and New York City, showed distinct clustering from known HRV-A and HRV-B species.
<xref rid="bib31" ref-type="bibr">
<sup>31</sup>
</xref>
Shortly after being described, these rhinoviruses were quickly reported worldwide in countries including Africa, Asia, Australia, America, and Europe and are now estimated to contribute to greater than 5% of tested specimens, highlighting their importance as a cause of respiratory tract infections.
<xref rid="bib31" ref-type="bibr">
<sup>31</sup>
</xref>
In Asia and the United States, HRV-C and HRV-A are the most prevalent of the three species. There appears to be a seasonality in HRV-C infections, with a peak incidence in the fall and winter, as well as the rainy season in tropical countries, but also occurring throughout the year.
<xref rid="bib31" ref-type="bibr">
<sup>31</sup>
</xref>
HRV-C infection has a predilection for the young, with most infections occurring in children less than 5 years of age, especially those below the age of 36 months.
<xref rid="bib32" ref-type="bibr">
<sup>32</sup>
</xref>
Part of the apparent rise in rhinovirus C infection may be due to improved virus detection methods that have led to an increase in its recognition as a cause of severe pneumonia in the elderly and the immunocompromised, specifically in pediatric oncology and patients who have undergone hematopoietic stem cell transplantation.</p>
</sec>
<sec id="s0200">
<title>Etiology</title>
<p id="p0455">HRV-C is a positive-sense, single-stranded nonenveloped RNA virus from the Picornaviridae family. It is one of the three species of HRV based on phylogenetic sequence analysis and is distinctly distinguished from other previously described species (HRV-A and HRV-B) on the basis of genomic features.
<xref rid="bib33" ref-type="bibr">
<sup>33</sup>
</xref>
</p>
</sec>
<sec id="s0205">
<title>Pathology/Pathogenesis</title>
<p id="p0460">In healthy individuals, HRV-C infection mostly causes rhinosinusitis through a neutrophilic inflammatory response resulting in increased vascular permeability and mucus hypersecretion in the upper respiratory tract. Cough, though less common, is thought to be due to direct infection of the bronchi or irritation from the posterior pharyngeal drainage of secretions.
<xref rid="bib34" ref-type="bibr">
<sup>34</sup>
</xref>
In patients with asthma or underlying lung disease, lower respiratory symptoms are more common. Despite the fact that rhinoviruses grow optimally at 33°C, which favors the upper respiratory tract, it is postulated that the warmer temperature in the lower respiratory tract is not an absolute barrier to replication. In many children with pneumonia, rhinoviruses have been isolated together with bacterial pathogens suggesting that HRV infection may lead to a predisposition to other respiratory pathogens.
<xref rid="bib34" ref-type="bibr">
<sup>34</sup>
</xref>
This has been supported by studies demonstrating that human tracheal epithelial cells had increased adherence to
<italic>Streptococcus pneumoniae</italic>
when coinfected by HRV.
<xref rid="bib35" ref-type="bibr">
<sup>35</sup>
</xref>
Other studies have also demonstrated that HRV-exposed macrophages had suboptimal responses to bacterial toll-like receptor agonists,
<xref rid="bib36" ref-type="bibr">
<sup>36</sup>
</xref>
which may predispose to secondary bacterial infections in humans.</p>
<p id="p0465">The true prevalence and pathogenic role of HRVs in the community has not been investigated in detail, and HRV has been found in lower airway fluids and cells of healthy volunteers.
<xref rid="bib37" ref-type="bibr">37</xref>
,
<xref rid="bib38" ref-type="bibr">38</xref>
Cohort studies, though, have shown high rates of HRV-C detection (up to 75%) in hospitalized children with lower respiratory illnesses.
<xref rid="bib39" ref-type="bibr">39</xref>
,
<xref rid="bib40" ref-type="bibr">40</xref>
,
<xref rid="bib41" ref-type="bibr">41</xref>
</p>
<p id="p0470">There are also increasing data linking wheezing secondary to HRV in early infancy with a higher risk of subsequent development of asthma compared with wheezing caused by other viruses. The Childhood Origins of Asthma (COAST) study showed that HRV-related wheezing in the first year of life led to a threefold risk of having asthma at 6 years. HRV wheezing in year 2 was associated with a more pronounced increase in asthma risk (odds ratio [OR] ~7), while HRV-related wheezing during year 3 of life was associated with an even dramatic (OR ~32) increase in asthma at school age.
<xref rid="bib42" ref-type="bibr">
<sup>42</sup>
</xref>
A similar birth cohort study in Australia reported that HRV-related wheezing in infancy was associated with an increased asthma risk at 5 years.
<xref rid="bib43" ref-type="bibr">
<sup>43</sup>
</xref>
The exact mechanisms by which HRV triggers or contributes to the inflammatory changes often seen in asthma is unclear, but it is suggested that it evolves from a combination of host susceptibility, other aeroallergen sensitization and the ability of HRV to activate proinflammatory and airway remodeling pathways.
<xref rid="bib44" ref-type="bibr">
<sup>44</sup>
</xref>
</p>
</sec>
<sec id="s0210">
<title>Clinical Features</title>
<p id="p0475">Symptoms of HRV-C infection typically occur after an incubation period of 12–72 hours. The disease is spread through aerosol or droplet transmission or direct person-to-person contact with contaminated secretions. Symptoms generally last 7–11 days.</p>
</sec>
<sec id="s0215">
<title>Symptoms</title>
<p id="p0480">Symptoms of HRV-C infection in children include fever greater than 38°C, and both upper and lower respiratory symptoms of cough, wheezing and shortness of breath.
<xref rid="bib45" ref-type="bibr">
<sup>45</sup>
</xref>
Infections commonly associated with HRV-C include acute upper respiratory tract infection, acute laryngitis, suppurative tonsillitis, otitis media, bronchitis, bronchiolitis, and bronchopneumonia. Although the clinical course is generally mild, HRV-C has been found to be more virulent than HRV-A
<xref rid="bib32" ref-type="bibr">
<sup>32</sup>
</xref>
and can run a more severe course in immunocompromised hosts—for example, children with hematologic malignancies, hematopoietic stem cell transplant recipients, and those on long-term steroid use.</p>
</sec>
<sec id="s0220">
<title>Physical Findings</title>
<p id="p0485">Common findings in HRV-C infection include upper respiratory tract signs of nasal congestion, cough, facial tenderness with sinus involvement, and inflammation of the tympanic membrane with otitis media. With lower respiratory tract involvement, symptoms such wheezing, cough, and dyspnea are common.</p>
</sec>
<sec id="s0225">
<title>Imaging, Pulmonary Function Tests, Laboratory Findings</title>
<p id="p0490">Chest x-ray findings include increased haziness in the perihilar or lower zone regions (
<xref rid="f0015" ref-type="fig">Fig. 28.2</xref>
). Consolidative changes and pleural effusions were less commonly noted in children and more commonly found in adult patients.
<xref rid="bib31" ref-type="bibr">
<sup>31</sup>
</xref>
<fig id="f0015">
<label>Fig. 28.2</label>
<caption>
<p>Chest x-ray of an 11-month-old infant with underlying decompensated liver disease and rhinovirus bronchiolitis. Bilateral perihilar infiltrates are demonstrated on this film.</p>
</caption>
<alt-text id="atte0015">Fig. 28.2</alt-text>
<graphic xlink:href="f028-002-9780323448871"></graphic>
</fig>
</p>
</sec>
<sec id="s0230">
<title>Diagnosis and Differential Diagnosis</title>
<p id="p0495">Conventional methods of viral testing such as immunofluorescence have often missed the presence of HRV-C; hence the recommended gold standard for the diagnosis of HRV-C infection is molecular testing with RT-PCR from nasopharyngeal or oropharyngeal secretions. Coinfection with bacterial infections is common, and the degree of rhinovirus identification in asymptomatic individuals in the community is not known. Hence isolation of rhinovirus C in a single sample with lack of clinical improvement over time may require analysis for the presence of a concomitant bacterial pathogen.</p>
</sec>
<sec id="s0235">
<title>Management and Treatment</title>
<p id="p0500">Similar to the other common viral upper respiratory tract pathogens already mentioned, treatment remains supportive and symptomatic. Pleconaril, an antiviral agent known to be effective against enterovirus and rhinovirus infections, seems to be an option for severe HRV-C infections. However, owing to the distinct genomic differences of HRV-C compared with the earlier discovered HRV-A, it is likely that HRV-C may be resistant to this drug.
<xref rid="bib46" ref-type="bibr">
<sup>46</sup>
</xref>
</p>
</sec>
<sec id="s0240">
<title>Prevention</title>
<p id="p0505">Despite the significant global burden of rhinovirus infection, no vaccine exists at this point because of antigenic heterogeneity between the greater than 150 rhinovirus strains.
<xref rid="bib47" ref-type="bibr">
<sup>47</sup>
</xref>
Strict hand hygiene and droplet precautions for patients with upper respiratory tract symptoms remain the mainstays of prevention.</p>
</sec>
<sec id="s0245">
<title>Prognosis</title>
<p id="p0510">Despite the initial reports of high mortality from rhinovirus C infections,
<xref rid="bib48" ref-type="bibr">48</xref>
,
<xref rid="bib49" ref-type="bibr">49</xref>
,
<xref rid="bib50" ref-type="bibr">50</xref>
most cases are associated with a good prognosis. A recent study of hematology and oncology patients did not detect any deaths associated with HRV-C infection.
<xref rid="bib48" ref-type="bibr">
<sup>48</sup>
</xref>
In a study from the Philippines, although rhinoviruses were the most common pathogens identified in children hospitalized with pneumonia, there were no fatalities associated with HRV infections, unlike influenza A.
<xref rid="bib51" ref-type="bibr">
<sup>51</sup>
</xref>
</p>
</sec>
</sec>
<sec id="s0250">
<title>Adenovirus</title>
<sec id="s0255">
<title>Epidemiology</title>
<p id="p0515">Adenovirus has been recognized as a pathogen since its discovery in 1953. However, recent interest in this virus as an emerging or (more accurately) reemerging respiratory pathogen arose from continued small outbreaks worldwide in both the United States and Asia. These have affected infants and young children, with 90% of them below the age of 60 months.
<xref rid="bib52" ref-type="bibr">
<sup>52</sup>
</xref>
Significantly, in Taiwan, there was a noted surge in cases in 2010–2011, triggering the establishment of a national surveillance system that found an acute rise of adenovirus-positive respiratory tract specimens from a baseline of 5.75% to a peak of 37.3% of all respiratory viruses isolated.
<xref rid="bib53" ref-type="bibr">
<sup>53</sup>
</xref>
Outbreaks across Asia appear to be linked by molecular epidemiology, although the mode of international spread is not clear.
<xref rid="bib54" ref-type="bibr">
<sup>54</sup>
</xref>
</p>
</sec>
<sec id="s0260">
<title>Etiology</title>
<p id="p0520">Adenoviruses are icosahedral, nonenveloped, medium-sized, double-stranded DNA viruses with more than 50 immunologically distinct serotypes; they belong to the family Adenoviridae. The serotypes linked to epidemic keratoconjunctivitis include types 8, 19, 37, 53, and 54. Those that typically cause acute respiratory disease are types 3, 4, and 7, while the enteric adenoviruses in children are mainly types 40 and 41.
<xref rid="bib55" ref-type="bibr">
<sup>55</sup>
</xref>
</p>
<p id="p0525">Adenoviruses are known to be resistant to common disinfectants and can remain on surfaces and in the water of pools and lakes for long periods of time.
<xref rid="bib56" ref-type="bibr">
<sup>56</sup>
</xref>
</p>
</sec>
<sec id="s0265">
<title>Transmission and Infection</title>
<p id="p0530">Adenovirus is spread by droplet transmission of respiratory secretions or direct contact with infected secretions (respiratory, urine, stool, or ocular). The virus can also spread through water and via the fecal-oral route. Shedding of the virus in stools has been documented for up to 2 years after an infection, and shedding can occur in the urine as well. The virus can cause latent infection in lymphoid tissue such as the adenoidal and tonsillar tissues of the throat,
<xref rid="bib57" ref-type="bibr">
<sup>57</sup>
</xref>
but the clinical significance of this is unclear.</p>
</sec>
<sec id="s0270">
<title>Clinical Features</title>
<p id="p0535">The incubation period of adenoviral infections ranges from 2 to 14 days. Infection has been known to cause pharyngitis, adenoiditis, tonsillitis, otitis media, and keratoconjunctivitis, commonly known as pharyngoconjunctival fever. Lower respiratory tract involvement with pneumonia and bronchitis has also been seen. Adenoviral infections are also known to cause extrapulmonary manifestations, which are commonly seen as acute gastroenteritis and acute hemorrhagic cystitis, with some cases of hepatitis and rarely meningoencephalitis. Infection is particularly severe and prolonged in the immunocompromised, especially those who have undergone hematologic stem cell transplantation.</p>
<p id="p0540">Certain serotypes, particularly 3, 7, and 21, have been reported to result in epidemics or fulminant events associated with long-term respiratory complications of bronchiolitis obliterans, bronchiectasis, and Swyer–James syndrome.
<xref rid="bib58" ref-type="bibr">58</xref>
,
<xref rid="bib59" ref-type="bibr">59</xref>
Bacterial coinfection in patients with adenoviral infections is noted to be rare, with a minimal role in the course of the disease in severe adenoviral infections.
<xref rid="bib53" ref-type="bibr">
<sup>53</sup>
</xref>
</p>
</sec>
<sec id="s0275">
<title>Symptoms</title>
<p id="p0545">The main symptoms of adenoviral infection include fever, cough, rhinorrhea, sore throat, and bilateral conjunctivitis, which can last from 3 to 5 days. Occasionally adenoviral infections cause prolonged fevers. Lower respiratory tract involvement is much less common. Extrapulmonary manifestations include diarrhea, abdominal pain, vomiting, and hematuria.</p>
</sec>
<sec id="s0280">
<title>Physical Findings</title>
<p id="p0550">Pharyngoconjunctival fever typically manifests with bilateral conjunctivitis, an injected pharynx and tonsils with significant bilateral cervical lymphadenopathy. In adenoviral pneumonia, findings include significant hypoxia, wheezing, and features of pulmonary consolidation.</p>
</sec>
<sec id="s0285">
<title>Imaging, Pulmonary Function Tests, Laboratory Findings</title>
<p id="p0555">Adenoviral infections can easily be confused with bacterial infections, as they are known to cause leukocytosis and neutrophilia on peripheral blood counts as well as elevated inflammatory markers.
<xref rid="bib59" ref-type="bibr">
<sup>59</sup>
</xref>
Transaminitis is also often noted with adenoviral infections. Because of high fevers, which can be more prolonged than with other viral causes, children with adenoviral infections are often presumptively treated for bacterial infections, with blood and urine cultures, and antibiotics before the diagnosis is made.</p>
<p id="p0560">For patients with lower respiratory tract involvement, chest x-ray findings typically show interstitial pulmonary infiltrates; less commonly, lobar consolidation is seen (
<xref rid="f0020" ref-type="fig">Fig. 28.3</xref>
).
<xref rid="bib59" ref-type="bibr">
<sup>59</sup>
</xref>
<fig id="f0020">
<label>Fig. 28.3</label>
<caption>
<p>Chest x-ray of an adolescent boy admitted for severe adenoviral pneumonitis with acute respiratory distress syndrome requiring support with extracorporeal membrane oxygenation. The figure demonstrates extensive bilateral pulmonary infiltrates consistent with severe pneumonitis.</p>
</caption>
<alt-text id="atte0020">Fig. 28.3</alt-text>
<graphic xlink:href="f028-003-9780323448871"></graphic>
</fig>
</p>
</sec>
<sec id="s0290">
<title>Diagnosis and Differential Diagnosis</title>
<p id="p0565">Pharyngoconjunctival fever in adenoviral infections can mimic other viral infections and is a common differential of the inflammatory condition Kawasaki disease due to conjunctival involvement as well as significant cervical lymphadenopathy. Gastroenteritis caused by adenoviral infections is similar to that caused by other viruses, such as astrovirus or norovirus. In immunocompromised patients, cytomegalovirus and Epstein-Barr virus are differentials for adenoviral enterocolitis.</p>
<p id="p0570">Detection of the virus can be performed via antigen detection, PCR, virus isolation, or serology. Antigen testing by direct fluorescent assay of respiratory secretions (nasopharyngeal) has been shown to have a sensitivity of about 62.5% and a specificity of up to 100%.
<xref rid="bib52" ref-type="bibr">
<sup>52</sup>
</xref>
PCR testing for adenovirus can be done on throat swabs, sputum, and rectal swabs with a reported sensitivity of 91%, 88%, and 86%, respectively. However, pleural effusion fluid has low pickup rates of adenovirus, estimated to be only 39%.
<xref rid="bib53" ref-type="bibr">
<sup>53</sup>
</xref>
Adenoviral PCR on blood and stool samples is most useful for immunocompromised patients in cases with severe manifestations.</p>
<p id="p0575">Blood serologic testing demonstrating a fourfold rise in the antibody titers between the acute and convalescent phases is the gold-standard diagnosis but is less commonly done owing to the development of more rapid diagnostic methods. Serotyping is not routinely performed and is used mainly for epidemiologic surveillance purposes.</p>
</sec>
<sec id="s0295">
<title>Management and Treatment</title>
<p id="p0580">No specific treatment exists for adenoviral infections in immunocompetent individuals, and most infections are self-limited. In immunocompromised hosts, the antiviral agent cidofovir has been used to treat severe infections, and several novel therapies have been explored.
<xref rid="bib60" ref-type="bibr">
<sup>60</sup>
</xref>
</p>
<p id="p0585">The treatment of postadenoviral bronchiolitis obliterans remains largely supportive, with oxygen supplementation and bronchodilators. Corticosteroids would be an ideal theoretical treatment, since bronchiolitis obliterans is largely an immune-mediated inflammatory response, but there have been mixed results. In a study of 31 children, the use of systemic steroids in adenoviral pneumonia did not alter the progression to bronchiolitis obliterans.
<xref rid="bib61" ref-type="bibr">
<sup>61</sup>
</xref>
Case series showing possible clinical benefit with intravenous methylprednisolone to treat bronchiolitis obliterans have been limited by small sample sizes and other confounders such as bronchodilator therapy. There have been no large clinical trials of the effectiveness of inhaled corticosteroids in the treatment of bronchiolitis obliterans.
<xref rid="bib62" ref-type="bibr">
<sup>62</sup>
</xref>
There is evidence suggesting that latent adenoviral infection causes eosinophilic airway inflammation, leading to the ineffectiveness of steroid treatment.
<xref rid="bib63" ref-type="bibr">
<sup>63</sup>
</xref>
</p>
</sec>
<sec id="s0300">
<title>Prevention</title>
<p id="p0590">Military recruits in the United States from 1971 to 1999 were routinely vaccinated against adenovirus due to the occurrence of outbreaks. After the cessation of vaccination, more cases became apparent. A new oral live attenuated adenoviral vaccine against types 4 and 7 was approved in 2011 for use in military personnel. However, no vaccine has been used in the general public.
<xref rid="bib56" ref-type="bibr">
<sup>56</sup>
</xref>
</p>
</sec>
<sec id="s0305">
<title>Prognosis</title>
<p id="p0595">Most immunocompetent individuals recover from the infection with no sequelae. However, severe cases of adenoviral pneumonia have been reported to result in bronchiectasis or bronchiolitis obliterans, and there have been deaths from severe adenoviral lung disease, mostly in patients with major underlying illnesses. Immunocompromised hematology and transplant patients have had fatal outcomes from disseminated adenoviral infections with liver failure, respiratory disease, and disseminated infection. Fatal cases have been associated particularly with serotype 7, but other serotypes have also been reported to be associated with fatalities.
<xref rid="bib53" ref-type="bibr">
<sup>53</sup>
</xref>
</p>
</sec>
</sec>
</body>
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