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<p><i><b>Haemophilus influenzae</b></i>, formerly called <b>Pfeiffer's bacillus</b> or <i><b>Bacillus influenzae</b></i>, is a non-motile <a class="mw-redirect" title="Gram-negative" href="/wiki/Gram-negative"><font color="#0645ad">Gram-negative</font></a> <a title="Bacillus (shape)" href="/wiki/Bacillus_(shape)"><font color="#0645ad">rod-shaped</font></a> <a class="mw-redirect" title="Bacterium" href="/wiki/Bacterium"><font color="#0645ad">bacterium</font></a> first described in 1892 by <a title="Richard Friedrich Johannes Pfeiffer" href="/wiki/Richard_Friedrich_Johannes_Pfeiffer"><font color="#0645ad">Richard Pfeiffer</font></a> during an <a title="Influenza" href="/wiki/Influenza"><font color="#0645ad">influenza</font></a> <a title="Pandemic" href="/wiki/Pandemic"><font color="#0645ad">pandemic</font></a>. A member of the <i><a title="Pasteurellaceae" href="/wiki/Pasteurellaceae"><font color="#0645ad">Pasteurellaceae</font></a></i> family, it is generally <a title="Aerobic organism" href="/wiki/Aerobic_organism"><font color="#0645ad">aerobic</font></a>, but can grow as a <a class="mw-redirect" title="Facultative anaerobe" href="/wiki/Facultative_anaerobe"><font color="#0645ad">facultative anaerobe</font></a>.<sup id="cite_ref-KuhnertChristensen_0-0" class="reference"><a href="#cite_note-KuhnertChristensen-0"><font size="2"><font color="#0645ad"><span>[</span>1<span>]</span></font></font></a></sup> <i>H. influenzae</i> was mistakenly considered to be the cause of <a title="Influenza" href="/wiki/Influenza"><font color="#0645ad">influenza</font></a> until 1933, when the viral <a title="Etiology" href="/wiki/Etiology"><font color="#0645ad">etiology</font></a> of the flu became apparent. Still, <i>H. influenzae</i> is responsible for a wide range of clinical diseases.</p>
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<p><b><span style="color: #000000">[[Haemophilus influenzae]],</span></b><span style="color: #000000">&nbsp;formerly called <b>Pfeiffer's bacillus</b> or <i><b>Bacillus influenzae</b></i>, is a non-motile Gram-negative rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the <i>Pasteurellaceae</i> family, it is generally aerobic, but can grow as a facultative anaerobe.<sup id="cite_ref-KuhnertChristensen_0-0" class="reference"><font size="2">[1]</font></sup> <i>H. influenzae</i> was mistakenly considered to be the cause of influenza until 1933, when the viral etiology of the flu became apparent. Still, <i>H. influenzae</i> is responsible for a wide range of clinical diseases.</span></p>
<p><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. The sequencing project was completed and published in 1995.</p>
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<p><span style="color: #000000"><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. The sequencing project was completed and published in 1995.</span></p>
<p>
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<p>&nbsp;</p>
<table id="toc" class="toc">
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<h2><span style="color: #000000"><span id="Serotypes" class="mw-headline">Serotypes</span></span></h2>
    <tbody>
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<p><span style="color: #000000">In 1930, 2 major categories of <i>H. influenzae</i> were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. There are six generally recognized types of encapsulated <i>H. influenzae</i>: a, b, c, d, e, and f.<sup id="cite_ref-Sherris_1-0" class="reference"><font size="2">[2]</font></sup> Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes, however they can be classified by multi-locus sequence typing. The pathogenesis of <i>H. influenzae</i> infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as epiglottitis, is known to be a major factor in virulence. Their capsule allows them to resist phagocytosis and complement-mediated lysis in the non-immune host. The unencapsulated strains are almost always less invasive, however they can produce an inflammatory response in humans which can lead to many symptoms. Vaccination with Hib conjugate vaccine is effective in preventing Hib infection. Several vaccines are now available for routine use against Hib, however vaccines are not yet available against NTHi.</span></p>
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<h2><span style="color: #000000"><span id="Diseases" class="mw-headline">Diseases</span></span></h2>
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            <div id="toctitle">
 
            <h2>Contents</h2>
 
            <span class="toctoggle"><font size="2">[</font><a id="togglelink" class="internal" href="#"><font color="#0645ad" size="2">hide</font></a><font size="2">]</font></span></div>
 
            <ul>
 
                <li class="toclevel-1 tocsection-1"><a href="#Serotypes"><font color="#0645ad"><span class="tocnumber">1</span> <span class="toctext">Serotypes</span></font></a></li>
 
                <li class="toclevel-1 tocsection-2"><a href="#Diseases"><font color="#0645ad"><span class="tocnumber">2</span> <span class="toctext">Diseases</span></font></a></li>
 
                <li class="toclevel-1 tocsection-3"><a href="#Diagnosis"><font color="#0645ad"><span class="tocnumber">3</span> <span class="toctext">Diagnosis</span></font></a>
 
                <ul>
 
                    <li class="toclevel-2 tocsection-4"><a href="#Culture"><font color="#0645ad"><span class="tocnumber">3.1</span> <span class="toctext">Culture</span></font></a></li>
 
                    <li class="toclevel-2 tocsection-5"><a href="#Latex_particle_agglutination"><font color="#0645ad"><span class="tocnumber">3.2</span> <span class="toctext">Latex particle agglutination</span></font></a></li>
 
                    <li class="toclevel-2 tocsection-6"><a href="#Molecular_Methods"><font color="#0645ad"><span class="tocnumber">3.3</span> <span class="toctext">Molecular Methods</span></font></a></li>
 
                </ul>
 
                </li>
 
                <li class="toclevel-1 tocsection-7"><a href="#Interaction_with_Streptococcus_pneumoniae"><font color="#0645ad"><span class="tocnumber">4</span> <span class="toctext">Interaction with Streptococcus pneumoniae</span></font></a></li>
 
                <li class="toclevel-1 tocsection-8"><a href="#Treatment"><font color="#0645ad"><span class="tocnumber">5</span> <span class="toctext">Treatment</span></font></a></li>
 
                <li class="toclevel-1 tocsection-9"><a href="#Sequencing"><font color="#0645ad"><span class="tocnumber">6</span> <span class="toctext">Sequencing</span></font></a></li>
 
                <li class="toclevel-1 tocsection-10"><a href="#See_also"><font color="#0645ad"><span class="tocnumber">7</span> <span class="toctext">See also</span></font></a></li>
 
                <li class="toclevel-1 tocsection-11"><a href="#References"><font color="#0645ad"><span class="tocnumber">8</span> <span class="toctext">References</span></font></a></li>
 
                <li class="toclevel-1 tocsection-12"><a href="#External_links"><font color="#0645ad"><span class="tocnumber">9</span> <span class="toctext">External links</span></font></a></li>
 
            </ul>
 
            </td>
 
        </tr>
 
    </tbody>
 
</table>
 
</p>
 
<h2><span id="Serotypes" class="mw-headline">Serotypes</span></h2>
 
<p>In 1930, 2 major categories of <i>H. influenzae</i> were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. There are six generally recognized types of encapsulated <i>H. influenzae</i>: a, b, c, d, e, and f.<sup id="cite_ref-Sherris_1-0" class="reference"><a href="#cite_note-Sherris-1"><font size="2"><font color="#0645ad"><span>[</span>2<span>]</span></font></font></a></sup> Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes, however they can be classified by multi-locus sequence typing. The <a title="Pathogenesis" href="/wiki/Pathogenesis"><font color="#0645ad">pathogenesis</font></a> of <i>H. influenzae</i> infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as <a title="Epiglottitis" href="/wiki/Epiglottitis"><font color="#0645ad">epiglottitis</font></a>, is known to be a major factor in virulence. Their capsule allows them to resist <a title="Phagocytosis" href="/wiki/Phagocytosis"><font color="#0645ad">phagocytosis</font></a> and complement-mediated <a title="Lysis" href="/wiki/Lysis"><font color="#0645ad">lysis</font></a> in the non-immune host. The unencapsulated strains are almost always less invasive, however they can produce an inflammatory response in humans which can lead to many symptoms. Vaccination with <a title="Hib vaccine" href="/wiki/Hib_vaccine"><font color="#0645ad">Hib conjugate vaccine</font></a> is effective in preventing Hib infection. Several vaccines are now available for routine use against Hib, however vaccines are not yet available against NTHi.</p>
 
<h2><span id="Diseases" class="mw-headline">Diseases</span></h2>
 
 
<p>
 
<p>
 
<table style="text-align: left; line-height: 1.5em; width: 22em; font-size: 88%" class="infobox" cellspacing="5">
 
<table style="text-align: left; line-height: 1.5em; width: 22em; font-size: 88%" class="infobox" cellspacing="5">
 
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         <tr>
 
         <tr>
             <th style="text-align: center; background-color: lightgrey; font-size: 125%; font-weight: bold" colspan="2">Haemophilus influenzae infection</th>
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             <th style="text-align: center; background-color: lightgrey; font-size: 125%; font-weight: bold" colspan="2"><span style="color: #000000">Haemophilus influenzae infection</span></th>
 
         </tr>
 
         </tr>
 
         <tr>
 
         <tr>
             <td style="text-align: center" colspan="2"><i>Classification and external resources</i></td>
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             <td style="text-align: center" colspan="2"><span style="color: #000000"><i>Classification and external resources</i></span></td>
 
         </tr>
 
         </tr>
 
         <tr>
 
         <tr>
             <th style="text-align: left" scope="row"><a class="mw-redirect" title="ICD" href="/wiki/ICD"><font color="#0645ad">ICD</font></a>-<a class="mw-redirect" title="List of ICD-10 codes" href="/wiki/List_of_ICD-10_codes"><font color="#0645ad">10</font></a></th>
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             <th style="text-align: left" scope="row"><span style="color: #000000">ICD-10</span></th>
             <td><a class="mw-redirect" title="ICD-10 Chapter A" href="/wiki/ICD-10_Chapter_A"><font color="#0645ad">A</font></a><a class="external text" href="http://apps.who.int/classifications/apps/icd/icd10online/?ga40.htm+a492" rel="nofollow"><font color="#3366bb">49.2</font></a></td>
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             <td><span style="color: #000000">A49.2</span></td>
 
         </tr>
 
         </tr>
 
         <tr>
 
         <tr>
             <th style="text-align: left" scope="row"><a class="mw-redirect" title="ICD" href="/wiki/ICD"><font color="#0645ad">ICD</font></a>-<a title="List of ICD-9 codes" href="/wiki/List_of_ICD-9_codes"><font color="#0645ad">9</font></a></th>
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             <th style="text-align: left" scope="row"><span style="color: #000000">ICD-9</span></th>
             <td><a class="external text" href="http://www.icd9data.com/getICD9Code.ashx?icd9=041.5" rel="nofollow"><font color="#3366bb">041.5</font></a></td>
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             <td><span style="color: #000000">041.5</span></td>
 
         </tr>
 
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         <tr>
 
         <tr>
             <th style="text-align: left" scope="row"><a title="Diseases Database" href="/wiki/Diseases_Database"><font color="#0645ad">DiseasesDB</font></a></th>
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             <th style="text-align: left" scope="row"><span style="color: #000000">DiseasesDB</span></th>
             <td><a class="external text" href="http://www.diseasesdatabase.com/ddb5570.htm" rel="nofollow"><font color="#3366bb">5570</font></a></td>
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             <td><span style="color: #000000">5570</span></td>
 
         </tr>
 
         </tr>
 
         <tr>
 
         <tr>
             <th style="text-align: left" scope="row"><a title="MedlinePlus" href="/wiki/MedlinePlus"><font color="#0645ad">MedlinePlus</font></a></th>
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             <th style="text-align: left" scope="row"><span style="color: #000000">MedlinePlus</span></th>
             <td><a class="external text" href="http://www.nlm.nih.gov/medlineplus/ency/article/000612.htm" rel="nofollow"><font color="#3366bb">000612</font></a> (Meningitis)</td>
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             <td><span style="color: #000000">000612 (Meningitis)</span></td>
 
         </tr>
 
         </tr>
 
         <tr>
 
         <tr>
             <th style="text-align: left" scope="row"><a title="EMedicine" href="/wiki/EMedicine"><font color="#0645ad">eMedicine</font></a></th>
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             <th style="text-align: left" scope="row"><span style="color: #000000">eMedicine</span></th>
             <td><a class="external text" href="http://search.medscape.com/emedicine-search?queryText=Haemophilus%20influenzae" rel="nofollow"><font color="#3366bb">topic list</font></a></td>
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             <td><span style="color: #000000">topic list</span></td>
 
         </tr>
 
         </tr>
 
     </tbody>
 
     </tbody>
 
</table>
 
</table>
 
</p>
 
</p>
<p>Most strains of <i>H. influenzae</i> are opportunistic pathogens - that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection or reduced immune function) create an opportunity.</p>
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<p><span style="color: #000000">Most strains of <i>H. influenzae</i> are opportunistic pathogens - that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection or reduced immune function) create an opportunity.</span></p>
<p>Naturally-acquired disease caused by <i>H. influenzae</i> seems to occur in humans only. In infants and young children, <i>H. influenzae</i> type b (Hib) causes <a title="Bacteremia" href="/wiki/Bacteremia"><font color="#0645ad">bacteremia</font></a>, <a title="Pneumonia" href="/wiki/Pneumonia"><font color="#0645ad">pneumonia</font></a>, and acute bacterial <a title="Meningitis" href="/wiki/Meningitis"><font color="#0645ad">meningitis</font></a>. Occasionally, it causes <a title="Cellulitis" href="/wiki/Cellulitis"><font color="#0645ad">cellulitis</font></a>, <a title="Osteomyelitis" href="/wiki/Osteomyelitis"><font color="#0645ad">osteomyelitis</font></a>, <a title="Epiglottitis" href="/wiki/Epiglottitis"><font color="#0645ad">epiglottitis</font></a>, and <a class="mw-redirect" title="Infectious arthritis" href="/wiki/Infectious_arthritis"><font color="#0645ad">infectious arthritis</font></a>. Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where vaccine is not widely used. Unencapsulated <i>H. influenzae</i> causes ear infections (<a title="Otitis media" href="/wiki/Otitis_media"><font color="#0645ad">otitis media</font></a>), eye infections (<a title="Conjunctivitis" href="/wiki/Conjunctivitis"><font color="#0645ad">conjunctivitis</font></a>), and <a title="Sinusitis" href="/wiki/Sinusitis"><font color="#0645ad">sinusitis</font></a> in children and is associated with <a title="Pneumonia" href="/wiki/Pneumonia"><font color="#0645ad">pneumonia</font></a>.</p>
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<p><span style="color: #000000">Naturally-acquired disease caused by <i>H. influenzae</i> seems to occur in humans only. In infants and young children, <i>H. influenzae</i> type b (Hib) causes bacteremia, pneumonia, and acute bacterial meningitis. Occasionally, it causes cellulitis, osteomyelitis, epiglottitis, and infectious arthritis. Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where vaccine is not widely used. Unencapsulated <i>H. influenzae</i> causes ear infections (otitis media), eye infections (conjunctivitis), and sinusitis in children and is associated with pneumonia.</span></p>
<h2><span id="Diagnosis" class="mw-headline">Diagnosis</span></h2>
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<h2><span style="color: #000000"><span id="Diagnosis" class="mw-headline">Diagnosis</span></span></h2>
 
<div class="thumb tright">
 
<div class="thumb tright">
<div style="width: 252px" class="thumbinner"><a class="image" href="/wiki/File:Haemophilus_influenzae_Gram.JPG"><img class="thumbimage" alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Haemophilus_influenzae_Gram.JPG/250px-Haemophilus_influenzae_Gram.JPG" width="250" height="209" /></a>
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<div style="width: 252px" class="thumbinner"><span style="color: #000000"><img class="thumbimage" alt="" width="250" height="209" src="http://upload.wikimedia.org/wikipedia/commons/thumb/6/67/Haemophilus_influenzae_Gram.JPG/250px-Haemophilus_influenzae_Gram.JPG" /> </span>
 
<div class="thumbcaption">
 
<div class="thumbcaption">
<div class="magnify"><a class="internal" title="Enlarge" href="/wiki/File:Haemophilus_influenzae_Gram.JPG"><img alt="" src="http://bits.wikimedia.org/skins-1.5/common/images/magnify-clip.png" width="15" height="11" /></a></div>
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<div class="magnify"><span style="color: #000000"><img alt="" width="15" height="11" src="http://bits.wikimedia.org/skins-1.5/common/images/magnify-clip.png" /></span></div>
<i>H. influenzae</i> Gram stain of a sputum sample, appear as Gram negative cocco-bacilli.<sup id="cite_ref-2" class="reference"><a href="#cite_note-2"><font size="1"><font color="#0645ad"><span>[</span>3<span>]</span></font></font></a></sup></div>
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<span style="color: #000000"><i>H. influenzae</i> Gram stain of a sputum sample, appear as Gram negative cocco-bacilli.<sup id="cite_ref-2" class="reference"><font size="1">[3]</font></sup></span></div>
 
</div>
 
</div>
 
</div>
 
</div>
<p>Clinical diagnosis of <i>H. influenzae</i> is typically performed by <a class="mw-redirect" title="Bacterial culture" href="/wiki/Bacterial_culture"><font color="#0645ad">bacterial culture</font></a> or <a class="mw-redirect" title="Latex particle agglutination" href="/wiki/Latex_particle_agglutination"><font color="#0645ad">latex particle agglutination</font></a>. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, <i>H. influenzae</i> cultured from the nasopharyngeal cavity or sputum would not indicate <i>H. influenzae</i> disease because these sites are colonized in disease free individuals.<sup id="cite_ref-Puri_1999_3-0" class="reference"><a href="#cite_note-Puri_1999-3"><font size="2"><font color="#0645ad"><span>[</span>4<span>]</span></font></font></a></sup> However <i>H. influenzae</i> isolated from cerebrospinal fluid or blood would indicate a <i>H. influenzae</i> infection.</p>
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<p><span style="color: #000000">Clinical diagnosis of <i>H. influenzae</i> is typically performed by bacterial culture or latex particle agglutination. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, <i>H. influenzae</i> cultured from the nasopharyngeal cavity or sputum would not indicate <i>H. influenzae</i> disease because these sites are colonized in disease free individuals.<sup id="cite_ref-Puri_1999_3-0" class="reference"><font size="2">[4]</font></sup> However <i>H. influenzae</i> isolated from cerebrospinal fluid or blood would indicate a <i>H. influenzae</i> infection.</span></p>
<h3><span id="Culture" class="mw-headline">Culture</span></h3>
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<h3><span style="color: #000000"><span id="Culture" class="mw-headline">Culture</span></span></h3>
<p>Bacterial culture of <i>H. influenzae</i> is performed on agar plates, preferably <a title="Chocolate agar" href="/wiki/Chocolate_agar"><font color="#0645ad">Chocolate agar</font></a>, plate with added <a title="Hemin" href="/wiki/Hemin"><font color="#0645ad">X</font></a>(Hemin) &amp; <a title="Nicotinamide adenine dinucleotide" href="/wiki/Nicotinamide_adenine_dinucleotide"><font color="#0645ad">V</font></a>(NAD) factors at 37&deg;C in an enriched CO2 incubator.<sup id="cite_ref-4" class="reference"><a href="#cite_note-4"><font size="2"><font color="#0645ad"><span>[</span>5<span>]</span></font></font></a></sup> Blood agar growth is only achieved as a satellite phenomenon around other bacteria. Colonies of <i>H. influenzae</i> appear as convex, smooth, pale, grey or transparent colonies. <a class="mw-redirect" title="Gram stain" href="/wiki/Gram_stain"><font color="#0645ad">Gram-stained</font></a> and microscopic observation of a specimen of <i>H. influenzae</i> will show Gram-negative, coccobacilli, with no specific arrangement. The cultured organism can be further characterized using <a title="Catalase" href="/wiki/Catalase"><font color="#0645ad">catalase</font></a> and <a title="Oxidase" href="/wiki/Oxidase"><font color="#0645ad">oxidase</font></a> tests, both of which should be positive. Further serological is necessary to distinguish the capsular polysaccharide and differentiate between <i>H. influenzae</i> b and non-encapsulated species.</p>
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<p><span style="color: #000000">Bacterial culture of <i>H. influenzae</i> is performed on agar plates, preferably Chocolate agar, plate with added X(Hemin) &amp; V(NAD) factors at 37&deg;C in an enriched CO2 incubator.<sup id="cite_ref-4" class="reference"><font size="2">[5]</font></sup> Blood agar growth is only achieved as a satellite phenomenon around other bacteria. Colonies of <i>H. influenzae</i> appear as convex, smooth, pale, grey or transparent colonies. Gram-stained and microscopic observation of a specimen of <i>H. influenzae</i> will show Gram-negative, coccobacilli, with no specific arrangement. The cultured organism can be further characterized using catalase and oxidase tests, both of which should be positive. Further serological is necessary to distinguish the capsular polysaccharide and differentiate between <i>H. influenzae</i> b and non-encapsulated species.</span></p>
<p>Although highly specific, bacterial culture of <i>H. influenzae</i> lacks in sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible.<sup id="cite_ref-John_1991_5-0" class="reference"><a href="#cite_note-John_1991-5"><font size="2"><font color="#0645ad"><span>[</span>6<span>]</span></font></font></a></sup> Beyond this, <i>H. influenzae</i> is a finicky bacterium to culture, and any modification of culture procedures can greatly reduce isolation rates. Poor quality of laboratories in developing countries has resulted in poor isolation rates of <i>H. influenzae</i>.</p>
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<p><span style="color: #000000">Although highly specific, bacterial culture of <i>H. influenzae</i> lacks in sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible.<sup id="cite_ref-John_1991_5-0" class="reference"><font size="2">[6]</font></sup> Beyond this, <i>H. influenzae</i> is a finicky bacterium to culture, and any modification of culture procedures can greatly reduce isolation rates. Poor quality of laboratories in developing countries has resulted in poor isolation rates of <i>H. influenzae</i>.</span></p>
<p>H. influenzae will grow in the hemolytic zone of Staphylococcus aureus on Blood Agar plates. The hemolysis of cells by Staph. aureus releases nutrients vital to the growth of H. influenzae. H. influenzae will not grow outside the hemolytic zone of Staph. aureus due to the lack of nutrients in these areas.</p>
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<p><span style="color: #000000">H. influenzae will grow in the hemolytic zone of Staphylococcus aureus on Blood Agar plates. The hemolysis of cells by Staph. aureus releases nutrients vital to the growth of H. influenzae. H. influenzae will not grow outside the hemolytic zone of Staph. aureus due to the lack of nutrients in these areas.</span></p>
<h3><span id="Latex_particle_agglutination" class="mw-headline">Latex particle agglutination</span></h3>
+
<h3><span style="color: #000000"><span id="Latex_particle_agglutination" class="mw-headline">Latex particle agglutination</span></span></h3>
<p><a class="mw-redirect" title="Latex particle agglutination test" href="/wiki/Latex_particle_agglutination_test"><font color="#0645ad">Latex particle agglutination test</font></a> (LAT) is a more sensitive method to detect <i>H. influenzae</i> than culture.<sup id="cite_ref-Kennedy_2007_6-0" class="reference"><a href="#cite_note-Kennedy_2007-6"><font size="2"><font color="#0645ad"><span>[</span>7<span>]</span></font></font></a></sup> Because the method relies on antigen rather than viable bacteria, the results are not disrupted by prior antibiotic use. It also has the added benefit of being much quicker than culture methods. However, antibiotic sensitivity is not possible with LAT, so a parallel culture is necessary.</p>
+
<p><span style="color: #000000">Latex particle agglutination test (LAT) is a more sensitive method to detect <i>H. influenzae</i> than culture.<sup id="cite_ref-Kennedy_2007_6-0" class="reference"><font size="2">[7]</font></sup> Because the method relies on antigen rather than viable bacteria, the results are not disrupted by prior antibiotic use. It also has the added benefit of being much quicker than culture methods. However, antibiotic sensitivity is not possible with LAT, so a parallel culture is necessary.</span></p>
<h3><span id="Molecular_Methods" class="mw-headline">Molecular Methods</span></h3>
+
<h3><span style="color: #000000"><span id="Molecular_Methods" class="mw-headline">Molecular Methods</span></span></h3>
<p><a title="Polymerase chain reaction" href="/wiki/Polymerase_chain_reaction"><font color="#0645ad">Polymerase chain reaction</font></a> (PCR) assays have been proven to be more sensitive than either LAT or culture tests and highly specific.<sup id="cite_ref-Kennedy_2007_6-1" class="reference"><a href="#cite_note-Kennedy_2007-6"><font size="2"><font color="#0645ad"><span>[</span>7<span>]</span></font></font></a></sup> However, PCR assays have not yet become routine in clinical settings. Counter-current immunoelectrophoresis has been shown to be an effective research diagnostic method, but has been largely supplanted by PCR.</p>
+
<p><span style="color: #000000">Polymerase chain reaction (PCR) assays have been proven to be more sensitive than either LAT or culture tests and highly specific.<sup id="cite_ref-Kennedy_2007_6-1" class="reference"><font size="2">[7]</font></sup> However, PCR assays have not yet become routine in clinical settings. Counter-current immunoelectrophoresis has been shown to be an effective research diagnostic method, but has been largely supplanted by PCR.</span></p>
<h2><span id="Interaction_with_Streptococcus_pneumoniae" class="mw-headline">Interaction with <i>Streptococcus pneumoniae</i></span></h2>
+
<h2><span style="color: #000000"><span id="Interaction_with_Streptococcus_pneumoniae" class="mw-headline">Interaction with <i>Streptococcus pneumoniae</i></span></span></h2>
<p>Both <i>H. influenzae</i> and <i><a title="Streptococcus pneumoniae" href="/wiki/Streptococcus_pneumoniae"><font color="#0645ad">S. pneumoniae</font></a></i> can be found in the upper respiratory system of humans. A study of competition in a laboratory revealed that, in a petri dish, <i>S. pneumoniae</i> always overpowered <i>H. influenzae</i> by attacking it with <a title="Hydrogen peroxide" href="/wiki/Hydrogen_peroxide"><font color="#0645ad">hydrogen peroxide</font></a> and stripping off the surface molecules that <i>H. influenzae</i> needs for survival.</p>
+
<p><span style="color: #000000">Both <i>H. influenzae</i> and <i>S. pneumoniae</i> can be found in the upper respiratory system of humans. A study of competition in a laboratory revealed that, in a petri dish, <i>S. pneumoniae</i> always overpowered <i>H. influenzae</i> by attacking it with hydrogen peroxide and stripping off the surface molecules that <i>H. influenzae</i> needs for survival.</span></p>
<p>When both bacteria are placed together into a nasal cavity, within 2 weeks, only <i>H. influenzae</i> survives. When either is placed separately into a nasal cavity, each one survives. Upon examining the upper respiratory tissue from mice exposed to both bacteria species, an extraordinarily large number of <a class="mw-redirect" title="Neutrophils" href="/wiki/Neutrophils"><font color="#0645ad">neutrophils</font></a> (immune cells) was found. In mice exposed to only one bacteria, the cells were not present.</p>
+
<p><span style="color: #000000">When both bacteria are placed together into a nasal cavity, within 2 weeks, only <i>H. influenzae</i> survives. When either is placed separately into a nasal cavity, each one survives. Upon examining the upper respiratory tissue from mice exposed to both bacteria species, an extraordinarily large number of neutrophils (immune cells) was found. In mice exposed to only one bacteria, the cells were not present.</span></p>
<p>Lab tests showed that neutrophils exposed to dead <i>H. influenzae</i> were more aggressive in attacking <i>S. pneumoniae</i> than unexposed neutrophils. Exposure to dead <i>H. influenzae</i> had no effect on live <i>H. influenzae</i>.</p>
+
<p><span style="color: #000000">Lab tests showed that neutrophils exposed to dead <i>H. influenzae</i> were more aggressive in attacking <i>S. pneumoniae</i> than unexposed neutrophils. Exposure to dead <i>H. influenzae</i> had no effect on live <i>H. influenzae</i>.</span></p>
<p>Two scenarios may be responsible for this response:</p>
+
<p><span style="color: #000000">Two scenarios may be responsible for this response:</span></p>
 
<ol>
 
<ol>
     <li>When <i>H. influenzae</i> is attacked by <i>S. pneumoniae</i>, it signals the immune system to attack the <i>S. pneumoniae</i></li>
+
     <li><span style="color: #000000">When <i>H. influenzae</i> is attacked by <i>S. pneumoniae</i>, it signals the immune system to attack the <i>S. pneumoniae</i> </span></li>
     <li>The combination of the two species together triggers an immune system response that is not set off by either species individually.</li>
+
     <li><span style="color: #000000">The combination of the two species together triggers an immune system response that is not set off by either species individually. </span></li>
 
</ol>
 
</ol>
<p>It is unclear why <i>H. influenzae</i> is not affected by the immune response.<sup id="cite_ref-Lysenko_2005_7-0" class="reference"><a href="#cite_note-Lysenko_2005-7"><font size="2"><font color="#0645ad"><span>[</span>8<span>]</span></font></font></a></sup></p>
+
<p><span style="color: #000000">It is unclear why <i>H. influenzae</i> is not affected by the immune response.<sup id="cite_ref-Lysenko_2005_7-0" class="reference"><font size="2">[8]</font></sup></span></p>
<h2><span id="Treatment" class="mw-headline">Treatment</span></h2>
+
<h2><span style="color: #000000"><span id="Treatment" class="mw-headline">Treatment</span></span></h2>
<p><i>Haemophilus influenzae</i> produces beta-lactamases, and it is also able to modify its penicillin binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases <a title="Cefotaxime" href="/wiki/Cefotaxime"><font color="#0645ad">cefotaxime</font></a> and <a title="Ceftriaxone" href="/wiki/Ceftriaxone"><font color="#0645ad">ceftriaxone</font></a> are the elected antibiotics, delivered directly into the bloodstream, and for the less severe cases an association of <a title="Ampicillin" href="/wiki/Ampicillin"><font color="#0645ad">ampicillin</font></a> and <a title="Sulbactam" href="/wiki/Sulbactam"><font color="#0645ad">sulbactam</font></a>, <a class="mw-redirect" title="Cephalosporins" href="/wiki/Cephalosporins"><font color="#0645ad">cephalosporins</font></a> of the second and third generation, or <a class="mw-redirect" title="Fluoroquinolones" href="/wiki/Fluoroquinolones"><font color="#0645ad">fluoroquinolones</font></a>. Macrolide antibiotics (e.g. <a title="Clarithromycin" href="/wiki/Clarithromycin"><font color="#0645ad">clarithromycin</font></a>) may be used in patients with a history of allergy to beta-lactam antibiotics.</p>
+
<p><span style="color: #000000"><i>Haemophilus influenzae</i> produces beta-lactamases, and it is also able to modify its penicillin binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases cefotaxime and ceftriaxone are the elected antibiotics, delivered directly into the bloodstream, and for the less severe cases an association of ampicillin and sulbactam, cephalosporins of the second and third generation, or fluoroquinolones. Macrolide antibiotics (e.g. clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics.</span></p>
<h2><span id="Sequencing" class="mw-headline">Sequencing</span></h2>
+
<h2><span style="color: #000000"><span id="Sequencing" class="mw-headline">Sequencing</span></span></h2>
<p><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. Haemophilus was chosen because one of the project leaders, Nobel laureate <a title="Hamilton Smith" href="/wiki/Hamilton_Smith"><font color="#0645ad">Hamilton Smith</font></a>, had been working on it for decades and was able to provide high-quality DNA libraries. The genome consists of 1,830,140 base pairs of DNA in a single circular chromosome that contains 1740 protein-coding genes, 58 transfer RNA genes <a class="mw-redirect" title="TRNA" href="/wiki/TRNA"><font color="#0645ad">tRNA</font></a>, and 18 other RNA genes. The sequencing method used was <a class="mw-redirect" title="Whole-genome shotgun" href="/wiki/Whole-genome_shotgun"><font color="#0645ad">Whole genome shotgun</font></a>. The sequencing project, completed and published in <i><a title="Science (journal)" href="/wiki/Science_(journal)"><font color="#0645ad">Science</font></a></i> in 1995, was conducted at <a title="The Institute for Genomic Research" href="/wiki/The_Institute_for_Genomic_Research"><font color="#0645ad">The Institute for Genomic Research</font></a>.<sup id="cite_ref-Fleichmann_1995_8-0" class="reference"><a href="#cite_note-Fleichmann_1995-8"><font size="2"><font color="#0645ad"><span>[</span>9<span>]</span></font></font></a></sup></p>
+
<p><span style="color: #000000"><i>H. influenzae</i> was the first free-living organism to have its entire genome sequenced. Haemophilus was chosen because one of the project leaders, Nobel laureate Hamilton Smith, had been working on it for decades and was able to provide high-quality DNA libraries. The genome consists of 1,830,140 base pairs of DNA in a single circular chromosome that contains 1740 protein-coding genes, 58 transfer RNA genes tRNA, and 18 other RNA genes. The sequencing method used was Whole genome shotgun. The sequencing project, completed and published in <i>Science</i> in 1995, was conducted at The Institute for Genomic Research.<sup id="cite_ref-Fleichmann_1995_8-0" class="reference"><font size="2">[9]</font></sup></span></p>
<h2><span id="See_also" class="mw-headline">See also</span></h2>
+
<h2><span style="color: #000000"><span id="See_also" class="mw-headline">See also</span></span></h2>
<p>
+
<p>&nbsp;</p>
<table style="border-bottom: #aaa 1px solid; border-left: #aaa 1px solid; background-color: #f9f9f9; border-top: #aaa 1px solid; border-right: #aaa 1px solid" class="metadata mbox-small plainlinks">
 
    <tbody>
 
        <tr>
 
            <td class="mbox-image"><img alt="" src="http://upload.wikimedia.org/wikipedia/commons/thumb/4/4a/Commons-logo.svg/30px-Commons-logo.svg.png" width="30" height="40" /></td>
 
            <td class="mbox-text">Wikimedia Commons has media related to: <i><b><a class="extiw" title="commons:Category:Haemophilus influenzae" href="http://commons.wikimedia.org/wiki/Category:Haemophilus_influenzae"><font color="#3366bb">Haemophilus influenzae</font></a></b></i></td>
 
        </tr>
 
    </tbody>
 
</table>
 
</p>
 
 
<ul>
 
<ul>
     <li><a title="Pasteurellaceae" href="/wiki/Pasteurellaceae"><font color="#0645ad">Pasteurellaceae</font></a></li>
+
     <li><span style="color: #000000">Pasteurellaceae </span></li>
     <li><a title="Maurice Hilleman" href="/wiki/Maurice_Hilleman"><font color="#0645ad">Maurice Hilleman</font></a></li>
+
     <li><span style="color: #000000">Maurice Hilleman </span></li>
     <li><a title="Hattie Alexander" href="/wiki/Hattie_Alexander"><font color="#0645ad">Hattie Alexander</font></a></li>
+
     <li><span style="color: #000000">Hattie Alexander </span></li>
     <li><a title="Hib vaccine" href="/wiki/Hib_vaccine"><font color="#0645ad">Hib vaccine</font></a></li>
+
     <li><span style="color: #000000">Hib vaccine </span></li>
     <li><a title="Haemophilus influenzae cellulitis" href="/wiki/Haemophilus_influenzae_cellulitis"><font color="#0645ad">Haemophilus influenzae cellulitis</font></a></li>
+
     <li><span style="color: #000000">Haemophilus influenzae cellulitis </span></li>
 
</ul>
 
</ul>
 
<h2><span id="References" class="mw-headline">References</span></h2>
 
<h2><span id="References" class="mw-headline">References</span></h2>
Line 122: Line 84:
 
     <li id="cite_note-KuhnertChristensen-0"><b><a href="#cite_ref-KuhnertChristensen_0-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Kuhnert P; Christensen H (editors). (2008). <i>Pasteurellaceae: Biology, Genomics and Molecular Aspects</i>. Caister Academic Press. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/978-1-904455-34-9" href="/wiki/Special:BookSources/978-1-904455-34-9"><font color="#0645ad">978-1-904455-34-9</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Pasteurellaceae%3A+Biology%2C+Genomics+and+Molecular+Aspects&amp;rft.aulast=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.au=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.date=2008&amp;rft.pub=Caister+Academic+Press&amp;rft.isbn=978-1-904455-34-9&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
     <li id="cite_note-KuhnertChristensen-0"><b><a href="#cite_ref-KuhnertChristensen_0-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Kuhnert P; Christensen H (editors). (2008). <i>Pasteurellaceae: Biology, Genomics and Molecular Aspects</i>. Caister Academic Press. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/978-1-904455-34-9" href="/wiki/Special:BookSources/978-1-904455-34-9"><font color="#0645ad">978-1-904455-34-9</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Pasteurellaceae%3A+Biology%2C+Genomics+and+Molecular+Aspects&amp;rft.aulast=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.au=Kuhnert+P%3B+Christensen+H+%28editors%29.&amp;rft.date=2008&amp;rft.pub=Caister+Academic+Press&amp;rft.isbn=978-1-904455-34-9&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
     <li id="cite_note-Sherris-1"><b><a href="#cite_ref-Sherris_1-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Ryan KJ; Ray CG (editors) (2004). <i>Sherris Medical Microbiology</i> (4th ed.). McGraw Hill. pp.&nbsp;396&ndash;401. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/0838585299" href="/wiki/Special:BookSources/0838585299"><font color="#0645ad">0838585299</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Sherris+Medical+Microbiology&amp;rft.aulast=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.au=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.date=2004&amp;rft.pages=pp.%26nbsp%3B396%26ndash%3B401&amp;rft.edition=4th&amp;rft.pub=McGraw+Hill&amp;rft.isbn=0838585299&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
     <li id="cite_note-Sherris-1"><b><a href="#cite_ref-Sherris_1-0"><font color="#0645ad">^</font></a></b> <span class="citation book">Ryan KJ; Ray CG (editors) (2004). <i>Sherris Medical Microbiology</i> (4th ed.). McGraw Hill. pp.&nbsp;396&ndash;401. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/0838585299" href="/wiki/Special:BookSources/0838585299"><font color="#0645ad">0838585299</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Sherris+Medical+Microbiology&amp;rft.aulast=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.au=Ryan+KJ%3B+Ray+CG+%28editors%29&amp;rft.date=2004&amp;rft.pages=pp.%26nbsp%3B396%26ndash%3B401&amp;rft.edition=4th&amp;rft.pub=McGraw+Hill&amp;rft.isbn=0838585299&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-2"><b><a href="#cite_ref-2"><font color="#0645ad">^</font></a></b> <span class="citation book">Behrman, Richard E.; Robert M Kliegman and Hal B. Jenson (2004). <a class="external text" href="http://books.google.com/?id=6a_lLbxRKwkC" rel="nofollow"><i><font color="#3366bb">Nelson Tratado de Pediatr&iacute;a</font></i></a>. Elsevier. p.&nbsp;904. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/8481747475" href="/wiki/Special:BookSources/8481747475"><font color="#0645ad">8481747475</font></a><span class="printonly">. <a class="external free" href="http://books.google.com/?id=6a_lLbxRKwkC" rel="nofollow"><font color="#3366bb">http://books.google.com/?id=6a_lLbxRKwkC</font></a></span><span class="reference-accessdate">. Retrieved 2009-09-11</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Nelson+Tratado+de+Pediatr%C3%ADa&amp;rft.aulast=Behrman&amp;rft.aufirst=Richard+E.&amp;rft.au=Behrman%2C%26%2332%3BRichard+E.&amp;rft.date=2004&amp;rft.pages=p.%26nbsp%3B904&amp;rft.pub=Elsevier&amp;rft.isbn=8481747475&amp;rft_id=http%3A%2F%2Fbooks.google.com%2F%3Fid%3D6a_lLbxRKwkC&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
+
     <li id="cite_note-2"><b><a href="#cite_ref-2"><font color="#0645ad">^</font></a></b> <span class="citation book">Behrman, Richard E.; Robert M Kliegman and Hal B. Jenson (2004). <a class="external text" rel="nofollow" href="http://books.google.com/?id=6a_lLbxRKwkC"><i><font color="#3366bb">Nelson Tratado de Pediatr&iacute;a</font></i></a>. Elsevier. p.&nbsp;904. <a title="International Standard Book Number" href="/wiki/International_Standard_Book_Number"><font color="#0645ad">ISBN</font></a>&nbsp;<a title="Special:BookSources/8481747475" href="/wiki/Special:BookSources/8481747475"><font color="#0645ad">8481747475</font></a><span class="printonly">. <a class="external free" rel="nofollow" href="http://books.google.com/?id=6a_lLbxRKwkC"><font color="#3366bb">http://books.google.com/?id=6a_lLbxRKwkC</font></a></span><span class="reference-accessdate">. Retrieved 2009-09-11</span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Nelson+Tratado+de+Pediatr%C3%ADa&amp;rft.aulast=Behrman&amp;rft.aufirst=Richard+E.&amp;rft.au=Behrman%2C%26%2332%3BRichard+E.&amp;rft.date=2004&amp;rft.pages=p.%26nbsp%3B904&amp;rft.pub=Elsevier&amp;rft.isbn=8481747475&amp;rft_id=http%3A%2F%2Fbooks.google.com%2F%3Fid%3D6a_lLbxRKwkC&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-Puri_1999-3"><b><a href="#cite_ref-Puri_1999_3-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Puri J, Talwar V, Juneja M, Agarwal KN, Gupta HC (1999). &quot;Prevalence of anti-microbial resistance among respiratory isolates of Haemophilus influenzae&quot;. <i>Indian Pediatr</i> <b>36</b> (10): 1029&ndash;32. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/10745313" rel="nofollow"><font color="#3366bb">10745313</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Prevalence+of+anti-microbial+resistance+among+respiratory+isolates+of+Haemophilus+influenzae&amp;rft.jtitle=Indian+Pediatr&amp;rft.aulast=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.au=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.date=1999&amp;rft.volume=36&amp;rft.issue=10&amp;rft.pages=1029%E2%80%9332&amp;rft_id=info:pmid/10745313&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
+
     <li id="cite_note-Puri_1999-3"><b><a href="#cite_ref-Puri_1999_3-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Puri J, Talwar V, Juneja M, Agarwal KN, Gupta HC (1999). &quot;Prevalence of anti-microbial resistance among respiratory isolates of Haemophilus influenzae&quot;. <i>Indian Pediatr</i> <b>36</b> (10): 1029&ndash;32. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/10745313"><font color="#3366bb">10745313</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Prevalence+of+anti-microbial+resistance+among+respiratory+isolates+of+Haemophilus+influenzae&amp;rft.jtitle=Indian+Pediatr&amp;rft.aulast=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.au=Puri+J%2C+Talwar+V%2C+Juneja+M%2C+Agarwal+KN%2C+Gupta+HC&amp;rft.date=1999&amp;rft.volume=36&amp;rft.issue=10&amp;rft.pages=1029%E2%80%9332&amp;rft_id=info:pmid/10745313&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
     <li id="cite_note-4"><b><a href="#cite_ref-4"><font color="#0645ad">^</font></a></b> <span class="citation Journal"><i>Generic protocol for population-based surveillance of Haemophilus influenzae type B</i>. World Health Organization. 1997. WHO/VRD/GEN/95.05.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Generic+protocol+for+population-based++surveillance+of+Haemophilus+influenzae+type+B&amp;rft.date=1997&amp;rft.pub=World+Health+Organization&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
     <li id="cite_note-4"><b><a href="#cite_ref-4"><font color="#0645ad">^</font></a></b> <span class="citation Journal"><i>Generic protocol for population-based surveillance of Haemophilus influenzae type B</i>. World Health Organization. 1997. WHO/VRD/GEN/95.05.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Abook&amp;rft.genre=book&amp;rft.btitle=Generic+protocol+for+population-based++surveillance+of+Haemophilus+influenzae+type+B&amp;rft.date=1997&amp;rft.pub=World+Health+Organization&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-John_1991-5"><b><a href="#cite_ref-John_1991_5-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">John TJ, Cherian T, Steinhoff MC, Simoes EA, John M (1991). &quot;Etiology of acute respiratory infections in children in tropical southern India&quot;. <i>Rev Infect Dis</i> <b>13</b>: Suppl 6:S463&ndash;9. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/1862277" rel="nofollow"><font color="#3366bb">1862277</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Etiology+of+acute+respiratory+infections+in+children+in+tropical+southern+India&amp;rft.jtitle=Rev+Infect+Dis&amp;rft.aulast=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.au=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.date=1991&amp;rft.volume=13&amp;rft.pages=Suppl+6%3AS463%E2%80%939&amp;rft_id=info:pmid/1862277&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
+
     <li id="cite_note-John_1991-5"><b><a href="#cite_ref-John_1991_5-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">John TJ, Cherian T, Steinhoff MC, Simoes EA, John M (1991). &quot;Etiology of acute respiratory infections in children in tropical southern India&quot;. <i>Rev Infect Dis</i> <b>13</b>: Suppl 6:S463&ndash;9. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/1862277"><font color="#3366bb">1862277</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Etiology+of+acute+respiratory+infections+in+children+in+tropical+southern+India&amp;rft.jtitle=Rev+Infect+Dis&amp;rft.aulast=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.au=John+TJ%2C+Cherian+T%2C+Steinhoff+MC%2C+Simoes+EA%2C+John+M&amp;rft.date=1991&amp;rft.volume=13&amp;rft.pages=Suppl+6%3AS463%E2%80%939&amp;rft_id=info:pmid/1862277&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-Kennedy_2007-6">^ <a href="#cite_ref-Kennedy_2007_6-0"><sup><i><b><font color="#0645ad" size="2">a</font></b></i></sup></a> <a href="#cite_ref-Kennedy_2007_6-1"><sup><i><b><font color="#0645ad" size="2">b</font></b></i></sup></a> <span class="citation Journal">Kennedy WA, Chang SJ, Purdy K, LE T, Kilgore PE, Kim JS et al. (2007). <a class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=2870670" rel="nofollow"><font color="#3366bb">&quot;Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture&quot;</font></a>. <i>Epidemiol Infect</i> <b>135</b> (7): 1217&ndash;26. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1017%2FS0950268806007734" rel="nofollow"><font color="#3366bb">10.1017/S0950268806007734</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/17274856" rel="nofollow"><font color="#3366bb">17274856</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Incidence+of+bacterial+meningitis+in+Asia+using+enhanced+CSF+testing%3A+polymerase+chain+reaction%2C+latex+agglutination+and+culture&amp;rft.jtitle=Epidemiol+Infect&amp;rft.aulast=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.au=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.date=2007&amp;rft.volume=135&amp;rft.issue=7&amp;rft.pages=1217%E2%80%9326&amp;rft_id=info:doi/10.1017%2FS0950268806007734&amp;rft_id=info:pmid/17274856&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
+
     <li id="cite_note-Kennedy_2007-6">^ <a href="#cite_ref-Kennedy_2007_6-0"><sup><i><b><font color="#0645ad" size="2">a</font></b></i></sup></a> <a href="#cite_ref-Kennedy_2007_6-1"><sup><i><b><font color="#0645ad" size="2">b</font></b></i></sup></a> <span class="citation Journal">Kennedy WA, Chang SJ, Purdy K, LE T, Kilgore PE, Kim JS et al. (2007). <a class="external text" rel="nofollow" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=2870670"><font color="#3366bb">&quot;Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture&quot;</font></a>. <i>Epidemiol Infect</i> <b>135</b> (7): 1217&ndash;26. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" rel="nofollow" href="http://dx.doi.org/10.1017%2FS0950268806007734"><font color="#3366bb">10.1017/S0950268806007734</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/17274856"><font color="#3366bb">17274856</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Incidence+of+bacterial+meningitis+in+Asia+using+enhanced+CSF+testing%3A+polymerase+chain+reaction%2C+latex+agglutination+and+culture&amp;rft.jtitle=Epidemiol+Infect&amp;rft.aulast=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.au=Kennedy+WA%2C+Chang+SJ%2C+Purdy+K%2C+LE+T%2C+Kilgore+PE%2C+Kim+JS+et+al.&amp;rft.date=2007&amp;rft.volume=135&amp;rft.issue=7&amp;rft.pages=1217%E2%80%9326&amp;rft_id=info:doi/10.1017%2FS0950268806007734&amp;rft_id=info:pmid/17274856&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-Lysenko_2005-7"><b><a href="#cite_ref-Lysenko_2005_7-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Lysenko E, Ratner A, Nelson A, Weiser J (2005). <a class="external text" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1238736" rel="nofollow"><font color="#3366bb">&quot;The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces&quot;</font></a>. <i>PLoS Pathog</i> <b>1</b> (1): e1. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1371%2Fjournal.ppat.0010001" rel="nofollow"><font color="#3366bb">10.1371/journal.ppat.0010001</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/16201010" rel="nofollow"><font color="#3366bb">16201010</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=The+role+of+innate+immune+responses+in+the+outcome+of+interspecies+competition+for+colonization+of+mucosal+surfaces&amp;rft.jtitle=PLoS+Pathog&amp;rft.aulast=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.au=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.date=2005&amp;rft.volume=1&amp;rft.issue=1&amp;rft.pages=e1&amp;rft_id=info:doi/10.1371%2Fjournal.ppat.0010001&amp;rft_id=info:pmid/16201010&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
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     <li id="cite_note-Lysenko_2005-7"><b><a href="#cite_ref-Lysenko_2005_7-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Lysenko E, Ratner A, Nelson A, Weiser J (2005). <a class="external text" rel="nofollow" href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&amp;artid=1238736"><font color="#3366bb">&quot;The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces&quot;</font></a>. <i>PLoS Pathog</i> <b>1</b> (1): e1. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" rel="nofollow" href="http://dx.doi.org/10.1371%2Fjournal.ppat.0010001"><font color="#3366bb">10.1371/journal.ppat.0010001</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/16201010"><font color="#3366bb">16201010</font></a>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=The+role+of+innate+immune+responses+in+the+outcome+of+interspecies+competition+for+colonization+of+mucosal+surfaces&amp;rft.jtitle=PLoS+Pathog&amp;rft.aulast=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.au=Lysenko+E%2C+Ratner+A%2C+Nelson+A%2C+Weiser+J&amp;rft.date=2005&amp;rft.volume=1&amp;rft.issue=1&amp;rft.pages=e1&amp;rft_id=info:doi/10.1371%2Fjournal.ppat.0010001&amp;rft_id=info:pmid/16201010&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
     <li id="cite_note-Fleichmann_1995-8"><b><a href="#cite_ref-Fleichmann_1995_8-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J (1995). <a class="external text" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496" rel="nofollow"><font color="#3366bb">&quot;Whole-genome random sequencing and assembly of Haemophilus influenzae Rd&quot;</font></a>. <i>Science</i> <b>269</b> (5223): 496&ndash;512. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" href="http://dx.doi.org/10.1126%2Fscience.7542800" rel="nofollow"><font color="#3366bb">10.1126/science.7542800</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" href="http://www.ncbi.nlm.nih.gov/pubmed/7542800" rel="nofollow"><font color="#3366bb">7542800</font></a><span class="printonly">. <a class="external free" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496" rel="nofollow"><font color="#3366bb">http://www.sciencemag.org/cgi/content/abstract/269/5223/496</font></a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Whole-genome+random+sequencing+and+assembly+of+Haemophilus+influenzae+Rd&amp;rft.jtitle=Science&amp;rft.aulast=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.au=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.date=1995&amp;rft.volume=269&amp;rft.issue=5223&amp;rft.pages=496%E2%80%93512&amp;rft_id=info:doi/10.1126%2Fscience.7542800&amp;rft_id=info:pmid/7542800&amp;rft_id=http%3A%2F%2Fwww.sciencemag.org%2Fcgi%2Fcontent%2Fabstract%2F269%2F5223%2F496&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
+
     <li id="cite_note-Fleichmann_1995-8"><b><a href="#cite_ref-Fleichmann_1995_8-0"><font color="#0645ad">^</font></a></b> <span class="citation Journal">Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J (1995). <a class="external text" rel="nofollow" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496"><font color="#3366bb">&quot;Whole-genome random sequencing and assembly of Haemophilus influenzae Rd&quot;</font></a>. <i>Science</i> <b>269</b> (5223): 496&ndash;512. <a title="Digital object identifier" href="/wiki/Digital_object_identifier"><font color="#0645ad">doi</font></a>:<a class="external text" rel="nofollow" href="http://dx.doi.org/10.1126%2Fscience.7542800"><font color="#3366bb">10.1126/science.7542800</font></a>. <a class="mw-redirect" title="PubMed Identifier" href="/wiki/PubMed_Identifier"><font color="#0645ad">PMID</font></a>&nbsp;<a class="external text" rel="nofollow" href="http://www.ncbi.nlm.nih.gov/pubmed/7542800"><font color="#3366bb">7542800</font></a><span class="printonly">. <a class="external free" rel="nofollow" href="http://www.sciencemag.org/cgi/content/abstract/269/5223/496"><font color="#3366bb">http://www.sciencemag.org/cgi/content/abstract/269/5223/496</font></a></span>.</span><span class="Z3988" title="ctx_ver=Z39.88-2004&amp;rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&amp;rft.genre=article&amp;rft.atitle=Whole-genome+random+sequencing+and+assembly+of+Haemophilus+influenzae+Rd&amp;rft.jtitle=Science&amp;rft.aulast=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.au=Fleischmann+R%2C+Adams+M%2C+White+O%2C+Clayton+R%2C+Kirkness+E%2C+Kerlavage+A%2C+Bult+C%2C+Tomb+J%2C+Dougherty+B%2C+Merrick+J&amp;rft.date=1995&amp;rft.volume=269&amp;rft.issue=5223&amp;rft.pages=496%E2%80%93512&amp;rft_id=info:doi/10.1126%2Fscience.7542800&amp;rft_id=info:pmid/7542800&amp;rft_id=http%3A%2F%2Fwww.sciencemag.org%2Fcgi%2Fcontent%2Fabstract%2F269%2F5223%2F496&amp;rfr_id=info:sid/en.wikipedia.org:Haemophilus_influenzae"><span style="display: none">&nbsp;</span></span></li>
 
</ol>
 
</ol>
 
</div>
 
</div>
 
<h2>&nbsp;<span id="External_links" class="mw-headline">External links</span></h2>
 
<h2>&nbsp;<span id="External_links" class="mw-headline">External links</span></h2>
 
<ul>
 
<ul>
     <li><a class="external text" href="http://www.who.int/immunization/topics/hib/en/index.html" rel="nofollow"><font color="#3366bb">Hib information</font></a> on the <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">World Health Organization</font></a> (WHO) site.</li>
+
     <li><a class="external text" rel="nofollow" href="http://www.who.int/immunization/topics/hib/en/index.html"><font color="#3366bb">Hib information</font></a> on the <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">World Health Organization</font></a> (WHO) site.</li>
     <li><a class="external text" href="http://www.cdc.gov/ncidod/dbmd/diseaseinfo/haeminfluserob_t.htm" rel="nofollow"><font color="#3366bb">Fact sheet</font></a> on the <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">Centers for Disease Control and Prevention</font></a> (CDC) site.</li>
+
     <li><a class="external text" rel="nofollow" href="http://www.cdc.gov/ncidod/dbmd/diseaseinfo/haeminfluserob_t.htm"><font color="#3366bb">Fact sheet</font></a> on the <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">Centers for Disease Control and Prevention</font></a> (CDC) site.</li>
     <li><a class="external text" href="http://www.hibaction.org" rel="nofollow"><font color="#3366bb">Hib Initiative</font></a> - from <a title="Johns Hopkins University" href="/wiki/Johns_Hopkins_University"><font color="#0645ad">Johns Hopkins University</font></a>, <a title="London School of Hygiene &amp; Tropical Medicine" href="/wiki/London_School_of_Hygiene_%26_Tropical_Medicine"><font color="#0645ad">London School of Hygiene &amp; Tropical Medicine</font></a>, <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">CDC</font></a> &amp; <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">WHO</font></a></li>
+
     <li><a class="external text" rel="nofollow" href="http://www.hibaction.org"><font color="#3366bb">Hib Initiative</font></a> - from <a title="Johns Hopkins University" href="/wiki/Johns_Hopkins_University"><font color="#0645ad">Johns Hopkins University</font></a>, <a title="London School of Hygiene &amp; Tropical Medicine" href="/wiki/London_School_of_Hygiene_%26_Tropical_Medicine"><font color="#0645ad">London School of Hygiene &amp; Tropical Medicine</font></a>, <a title="Centers for Disease Control and Prevention" href="/wiki/Centers_for_Disease_Control_and_Prevention"><font color="#0645ad">CDC</font></a> &amp; <a title="World Health Organization" href="/wiki/World_Health_Organization"><font color="#0645ad">WHO</font></a></li>
     <li><a class="external text" href="http://www.worldpneumoniaday.org" rel="nofollow"><font color="#3366bb">November 2nd: World Pneumonia Day Website</font></a></li>
+
     <li><a class="external text" rel="nofollow" href="http://www.worldpneumoniaday.org"><font color="#3366bb">November 2nd: World Pneumonia Day Website</font></a></li>
 
</ul>
 
</ul>
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<p>&nbsp;</p>
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Latest revision as of 14:25, 14 November 2010

Haemophilus influenzae, formerly called Pfeiffer's bacillus or Bacillus influenzae, is a non-motile Gram-negative rod-shaped bacterium first described in 1892 by Richard Pfeiffer during an influenza pandemic. A member of the Pasteurellaceae family, it is generally aerobic, but can grow as a facultative anaerobe.[1] H. influenzae was mistakenly considered to be the cause of influenza until 1933, when the viral etiology of the flu became apparent. Still, H. influenzae is responsible for a wide range of clinical diseases.

H. influenzae was the first free-living organism to have its entire genome sequenced. The sequencing project was completed and published in 1995.

 

Serotypes

In 1930, 2 major categories of H. influenzae were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. There are six generally recognized types of encapsulated H. influenzae: a, b, c, d, e, and f.[2] Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes, however they can be classified by multi-locus sequence typing. The pathogenesis of H. influenzae infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as epiglottitis, is known to be a major factor in virulence. Their capsule allows them to resist phagocytosis and complement-mediated lysis in the non-immune host. The unencapsulated strains are almost always less invasive, however they can produce an inflammatory response in humans which can lead to many symptoms. Vaccination with Hib conjugate vaccine is effective in preventing Hib infection. Several vaccines are now available for routine use against Hib, however vaccines are not yet available against NTHi.

Diseases

Haemophilus influenzae infection
Classification and external resources
ICD-10 A49.2
ICD-9 041.5
DiseasesDB 5570
MedlinePlus 000612 (Meningitis)
eMedicine topic list

Most strains of H. influenzae are opportunistic pathogens - that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection or reduced immune function) create an opportunity.

Naturally-acquired disease caused by H. influenzae seems to occur in humans only. In infants and young children, H. influenzae type b (Hib) causes bacteremia, pneumonia, and acute bacterial meningitis. Occasionally, it causes cellulitis, osteomyelitis, epiglottitis, and infectious arthritis. Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where vaccine is not widely used. Unencapsulated H. influenzae causes ear infections (otitis media), eye infections (conjunctivitis), and sinusitis in children and is associated with pneumonia.

Diagnosis

H. influenzae Gram stain of a sputum sample, appear as Gram negative cocco-bacilli.[3]

Clinical diagnosis of H. influenzae is typically performed by bacterial culture or latex particle agglutination. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, H. influenzae cultured from the nasopharyngeal cavity or sputum would not indicate H. influenzae disease because these sites are colonized in disease free individuals.[4] However H. influenzae isolated from cerebrospinal fluid or blood would indicate a H. influenzae infection.

Culture

Bacterial culture of H. influenzae is performed on agar plates, preferably Chocolate agar, plate with added X(Hemin) & V(NAD) factors at 37°C in an enriched CO2 incubator.[5] Blood agar growth is only achieved as a satellite phenomenon around other bacteria. Colonies of H. influenzae appear as convex, smooth, pale, grey or transparent colonies. Gram-stained and microscopic observation of a specimen of H. influenzae will show Gram-negative, coccobacilli, with no specific arrangement. The cultured organism can be further characterized using catalase and oxidase tests, both of which should be positive. Further serological is necessary to distinguish the capsular polysaccharide and differentiate between H. influenzae b and non-encapsulated species.

Although highly specific, bacterial culture of H. influenzae lacks in sensitivity. Use of antibiotics prior to sample collection greatly reduces the isolation rate by killing the bacteria before identification is possible.[6] Beyond this, H. influenzae is a finicky bacterium to culture, and any modification of culture procedures can greatly reduce isolation rates. Poor quality of laboratories in developing countries has resulted in poor isolation rates of H. influenzae.

H. influenzae will grow in the hemolytic zone of Staphylococcus aureus on Blood Agar plates. The hemolysis of cells by Staph. aureus releases nutrients vital to the growth of H. influenzae. H. influenzae will not grow outside the hemolytic zone of Staph. aureus due to the lack of nutrients in these areas.

Latex particle agglutination

Latex particle agglutination test (LAT) is a more sensitive method to detect H. influenzae than culture.[7] Because the method relies on antigen rather than viable bacteria, the results are not disrupted by prior antibiotic use. It also has the added benefit of being much quicker than culture methods. However, antibiotic sensitivity is not possible with LAT, so a parallel culture is necessary.

Molecular Methods

Polymerase chain reaction (PCR) assays have been proven to be more sensitive than either LAT or culture tests and highly specific.[7] However, PCR assays have not yet become routine in clinical settings. Counter-current immunoelectrophoresis has been shown to be an effective research diagnostic method, but has been largely supplanted by PCR.

Interaction with Streptococcus pneumoniae

Both H. influenzae and S. pneumoniae can be found in the upper respiratory system of humans. A study of competition in a laboratory revealed that, in a petri dish, S. pneumoniae always overpowered H. influenzae by attacking it with hydrogen peroxide and stripping off the surface molecules that H. influenzae needs for survival.

When both bacteria are placed together into a nasal cavity, within 2 weeks, only H. influenzae survives. When either is placed separately into a nasal cavity, each one survives. Upon examining the upper respiratory tissue from mice exposed to both bacteria species, an extraordinarily large number of neutrophils (immune cells) was found. In mice exposed to only one bacteria, the cells were not present.

Lab tests showed that neutrophils exposed to dead H. influenzae were more aggressive in attacking S. pneumoniae than unexposed neutrophils. Exposure to dead H. influenzae had no effect on live H. influenzae.

Two scenarios may be responsible for this response:

  1. When H. influenzae is attacked by S. pneumoniae, it signals the immune system to attack the S. pneumoniae
  2. The combination of the two species together triggers an immune system response that is not set off by either species individually.

It is unclear why H. influenzae is not affected by the immune response.[8]

Treatment

Haemophilus influenzae produces beta-lactamases, and it is also able to modify its penicillin binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases cefotaxime and ceftriaxone are the elected antibiotics, delivered directly into the bloodstream, and for the less severe cases an association of ampicillin and sulbactam, cephalosporins of the second and third generation, or fluoroquinolones. Macrolide antibiotics (e.g. clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics.

Sequencing

H. influenzae was the first free-living organism to have its entire genome sequenced. Haemophilus was chosen because one of the project leaders, Nobel laureate Hamilton Smith, had been working on it for decades and was able to provide high-quality DNA libraries. The genome consists of 1,830,140 base pairs of DNA in a single circular chromosome that contains 1740 protein-coding genes, 58 transfer RNA genes tRNA, and 18 other RNA genes. The sequencing method used was Whole genome shotgun. The sequencing project, completed and published in Science in 1995, was conducted at The Institute for Genomic Research.[9]

See also

 

  • Pasteurellaceae
  • Maurice Hilleman
  • Hattie Alexander
  • Hib vaccine
  • Haemophilus influenzae cellulitis

References

  1. ^ Kuhnert P; Christensen H (editors). (2008). Pasteurellaceae: Biology, Genomics and Molecular Aspects. Caister Academic Press. ISBN 978-1-904455-34-9. 
  2. ^ Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. pp. 396–401. ISBN 0838585299. 
  3. ^ Behrman, Richard E.; Robert M Kliegman and Hal B. Jenson (2004). Nelson Tratado de Pediatría. Elsevier. p. 904. ISBN 8481747475. http://books.google.com/?id=6a_lLbxRKwkC. Retrieved 2009-09-11. 
  4. ^ Puri J, Talwar V, Juneja M, Agarwal KN, Gupta HC (1999). "Prevalence of anti-microbial resistance among respiratory isolates of Haemophilus influenzae". Indian Pediatr 36 (10): 1029–32. PMID 10745313. 
  5. ^ Generic protocol for population-based surveillance of Haemophilus influenzae type B. World Health Organization. 1997. WHO/VRD/GEN/95.05. 
  6. ^ John TJ, Cherian T, Steinhoff MC, Simoes EA, John M (1991). "Etiology of acute respiratory infections in children in tropical southern India". Rev Infect Dis 13: Suppl 6:S463–9. PMID 1862277. 
  7. ^ a b Kennedy WA, Chang SJ, Purdy K, LE T, Kilgore PE, Kim JS et al. (2007). "Incidence of bacterial meningitis in Asia using enhanced CSF testing: polymerase chain reaction, latex agglutination and culture". Epidemiol Infect 135 (7): 1217–26. doi:10.1017/S0950268806007734. PMID 17274856. 
  8. ^ Lysenko E, Ratner A, Nelson A, Weiser J (2005). "The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces". PLoS Pathog 1 (1): e1. doi:10.1371/journal.ppat.0010001. PMID 16201010. 
  9. ^ Fleischmann R, Adams M, White O, Clayton R, Kirkness E, Kerlavage A, Bult C, Tomb J, Dougherty B, Merrick J (1995). "Whole-genome random sequencing and assembly of Haemophilus influenzae Rd". Science 269 (5223): 496–512. doi:10.1126/science.7542800. PMID 7542800. http://www.sciencemag.org/cgi/content/abstract/269/5223/496. 

 External links