First Identification and Description of Rickettsioses and Q Fever as Causes of Acute Febrile Illness in Nicaragua

<div><p>Background</p><p>Rickettsial infections and Q fever present similarly to other acute febrile illnesses, but are infrequently diagnosed because of limited diagnostic tools. Despite sporadic reports, rickettsial infections and Q fever have not been prospectively studied in Central America.</p><p>Methodology/Principal Findings</p><p>We enrolled consecutive patients presenting with undifferentiated fever in western Nicaragua and collected epidemiologic and clinical data and acute and convalescent sera. We used ELISA for screening and paired sera to confirm acute (≥4-fold rise in titer) spotted fever and typhus group rickettsial infections and Q fever as well as past (stable titer) infections. Characteristics associated with both acute and past infection were assessed.</p><p>Conclusions/Significance</p><p>We enrolled 825 patients and identified acute rickettsial infections and acute Q fever in 0.9% and 1.3%, respectively. Clinical features were non-specific and neither rickettsial infections nor Q fever were considered or treated. Further study is warranted to define the burden of these infections in Central America.</p></div

Flow diagram depicting approach to serological evaluation of convalescent and acute phase sera for IgG antibodies to spotted fever group rickettsiae, including ELISA and IFA for <i>R</i>. <i>rickettsii</i> and IFA for <i>R</i>. <i>parkeri</i>.

<p>Note that the IFA substrate slides used resulted in simultaneous tests for both <i>R</i>. <i>rickettsii</i> and <i>R</i>. <i>typhi</i>; those samples identified with <i>R</i>. <i>typhi</i> IFA antibodies were then included in the <i>R</i>. <i>typhi</i> tally (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005185#pntd.0005185.g002" target="_blank">Fig 2</a>) if not <i>R</i>. <i>typhi</i> ELISA reactive.</p

Epidemiologic characteristics of patients with definitive serologic evidence of Q fever vs. no Q fever, Nicaragua

<p>Epidemiologic characteristics of patients with definitive serologic evidence of Q fever vs. no Q fever, Nicaragua</p

Clinical characteristics of febrile patients with confirmed acute rickettsial infection vs. no acute rickettsial infection, Nicaragua.

<p>Clinical characteristics of febrile patients with confirmed acute rickettsial infection vs. no acute rickettsial infection, Nicaragua.</p

Flow diagram depicting approach to serological evaluation of convalescent and acute phase sera for IgG antibodies to <i>R</i>. <i>typhi</i>, including ELISA and IFA.

<p>Note that the IFA substrate slides used resulted in simultaneous tests for both <i>R</i>. <i>rickettsii</i> and <i>R</i>. <i>typhi</i>; those samples identified with <i>R</i>. <i>rickettsii</i> IFA antibodies were then included in the <i>R</i>. <i>rickettsii</i> tally (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005185#pntd.0005185.g001" target="_blank">Fig 1</a>) if not <i>R</i>. <i>rickettsii</i> ELISA reactive.</p

Clinical characteristics of febrile patients with acute Q fever vs. no acute Q fever, Nicaragua.

<p>Clinical characteristics of febrile patients with acute Q fever vs. no acute Q fever, Nicaragua.</p

Gene Expression Profiles Link Respiratory Viral Infection, Platelet Response to Aspirin, and Acute Myocardial Infarction

<div><p>Background</p><p>Influenza infection is associated with myocardial infarction (MI), suggesting that respiratory viral infection may induce biologic pathways that contribute to MI. We tested the hypotheses that 1) a validated blood gene expression signature of respiratory viral infection (viral GES) was associated with MI and 2) respiratory viral exposure changes levels of a validated platelet gene expression signature (platelet GES) of platelet function in response to aspirin that is associated with MI.</p><p>Methods</p><p>A previously defined viral GES was projected into blood RNA data from 594 patients undergoing elective cardiac catheterization and used to classify patients as having evidence of viral infection or not and tested for association with acute MI using logistic regression. A previously defined platelet GES was projected into blood RNA data from 81 healthy subjects before and after exposure to four respiratory viruses: Respiratory Syncytial Virus (RSV) (n=20), Human Rhinovirus (HRV) (n=20), Influenza A virus subtype H1N1 (H1N1) (n=24), Influenza A Virus subtype H3N2 (H3N2) (n=17). We tested for the change in platelet GES with viral exposure using linear mixed-effects regression and by symptom status.</p><p>Results</p><p>In the catheterization cohort, 32 patients had evidence of viral infection based upon the viral GES, of which 25% (8/32) had MI versus 12.2% (69/567) among those without evidence of viral infection (OR 2.3; CI [1.03-5.5], p=0.04). In the infection cohorts, only H1N1 exposure increased platelet GES over time (time course p-value = 1e-04).</p><p>Conclusions</p><p>A viral GES of non-specific, respiratory viral infection was associated with acute MI; 18% of the top 49 genes in the viral GES are involved with hemostasis and/or platelet aggregation. Separately, H1N1 exposure, but not exposure to other respiratory viruses, increased a platelet GES previously shown to be associated with MI. Together, these results highlight specific genes and pathways that link viral infection, platelet activation, and MI especially in the case of H1N1 influenza infection.</p></div

Unsuspected Leptospirosis Is a Cause of Acute Febrile Illness in Nicaragua

<div><p>Background</p><p>Epidemic severe leptospirosis was recognized in Nicaragua in 1995, but unrecognized epidemic and endemic disease remains unstudied.</p><p>Methodology/Principal Findings</p><p>To determine the burden of and risk factors associated with symptomatic leptospirosis in Nicaragua, we prospectively studied patients presenting with fever at a large teaching hospital. Epidemiologic and clinical features were systematically recorded, and paired sera tested by IgM-ELISA to identify patients with probable and possible acute leptospirosis. Microscopic Agglutination Test and PCR were used to confirm acute leptospirosis. Among 704 patients with paired sera tested by MAT, 44 had acute leptospirosis. Patients with acute leptospirosis were more likely to present during rainy months and to report rural residence and fresh water exposure. The sensitivity of clinical impression and acute-phase IgM detected by ELISA were poor.</p><p>Conclusions/Significance</p><p>Leptospirosis is a common (6.3%) but unrecognized cause of acute febrile illness in Nicaragua. Rapid point-of-care tests to support early diagnosis and treatment as well as tests to support population-based studies to delineate the epidemiology, incidence, and clinical spectrum of leptospirosis, both ideally pathogen-based, are needed.</p></div

Association of selected viral gene expression signature genes with myocardial infarction.

<p>Genes from the viral gene expression signature (viral GES) were selected based on their role in platelet activation, thrombosis, and hemostasis (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132259#pone.0132259.t004" target="_blank">Table 4</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132259#sec021" target="_blank">Discussion</a>). The association between gene expression and myocardial infarction (MI) is plotted as the standardized odds ratio (y-axis) for each gene (x-axis). Higher odds ratio imply that higher gene expression is associated with higher risk of MI. * indicate genes that are significantly (p-value < 0.05) associated with MI.</p

Study participants with a diagnosis of confirmed acute leptospirosis, Nicaragua 2008–9.

<p>Study participants with a diagnosis of confirmed acute leptospirosis, Nicaragua 2008–9.</p