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1.  Changes in Human Serum Amyloid A and C-Reactive Protein after Etiocholanolone-Induced Inflammation 
Journal of Clinical Investigation  1978;61(2):390-394.
Secondary amyloidosis is a complication of diseases characterized by recurrent acute inflammation. In this study, a standardized stimulus which induced fever and inflammation was given to six normal subjects (19-24 yr old) to follow the fluctuation in concentration of serum amyloid A (SAA), the precursor of the secondary amyloid fibril protein. After a single intramuscular injection of etiocholanolone (0.3 mg/kg), blood samples were drawn twice a day for 12 days for determination of SAA by solid phase radioimmunoassay. From a base line of <100 μg/ml, the SAA concentration began rising within 12 h to a maximum value at about 48 h of 1,350-1,800 μg/ml in three males and 380-900 μg/ml in three females and returned to base line by 4-5 days. The SAA response showed a similar time response to C-reactive protein (CRP), a well-documented acute phase protein which was assayed semiquantitatively by capillary tube precipitin reaction. CRP, but not SAA, showed a quantitative correlation with the amount of fever induced by etiocholanolone. One subject exhibited a second rise in SAA and CRP concentrations after acute over-indulgence with alcohol, suggesting that acute liver damage may have caused an acute phase reaction. Thus, a controlled episode of fever and inflammation produced a prompt and prolonged elevation of SAA and CRP concentrations. Unlike SAA, CRP has not been implicated in the pathogenesis of amyloidosis, although its relationship to the P component of amyloid has recently been established.
PMCID: PMC372549  PMID: 621279
2.  Studies on steroid fever II. Pyrogenic and anti-pyrogenic activity in vitro of some endogenous steroids of man 
Journal of Clinical Investigation  1970;49(12):2418-2426.
The pyrogenic properties of some C-19 and C-21 steroids were examined by in vitro incubation of human blood leukocytes with serum-buffer solutions of the steroids and injection of the 18-hr supernatants into rabbits. In previous studies this method demonstrated release of leukocyte endogenous pyrogen by etiocholanolone. With two exceptions, steroids known to cause fever in man, such as 11β-OH etiocholanolone and 3α-hydroxy-5β-pregnane-20-one were also pyrogenic in vitro. All steroids tested which are nonpyrogenic in man, such as androsterone, 3β-OH etiocholanolone, and 3α, 17α-dihydroxy-5β-pregnan-20-one were also nonpyrogenic in vitro. Solubility in aqueous solution did not correlate with pyrogenic capacity.
Inhibition of pyrogen release from human leukocytes in vitro by hydrocortisone and estradiol was demonstrated. Hydrocortisone-treated leukocytes released less pyrogen than did normal leukocytes when stimulated either by etiocholanolone or by phagocytosis of heat-killed staphylococci. On the other hand, estradiol-treated blood leukocytes and mononuclear cells showed significant suppression of pyrogen release when phagocytosis, but not etiocholanolone, was used as the stimulus. When blood cells were incubated with progesterone, greater than normal amounts of pyrogen were released following phagocytosis, and the inhibiting effect of estradiol could be partially reversed. Neither estradiol nor hydrocortisone appeared to act on rabbit leukocytes.
These studies indicate that a variety of naturally-occurring steroids may alter pyrogen release from leukocytes. Alterations in steroid balance in man may influence normal temperature regulation and contribute to clinical fevers.
PMCID: PMC322743  PMID: 5480865
3.  Studies on steroid fever 
Journal of Clinical Investigation  1968;47(1):107-117.
When a serum-buffer solution of etiocholanolone is incubated with human blood leukocytes in vitro, a pyrogen is released. Like endogenous pyrogen of leukocyte origin, this pyrogen produces prompt monophasic fevers in rabbits, does not induce fever tolerance when given daily, and is inactivated by trypsin. In many respects, the characteristics of the in vitro reaction resemble experimental steroid-induced fever. For example, release of pyrogen varies directly with the concentration of steroid. 4-8 hr of contact between steroid and leukocyte is required for activation of the cell. Rabbit leukocytes are not activated by etiocholanolone. Finally, androsterone, the 5α-isomer of etiocholanolone, does not induce pyrogen release in vitro. These studies suggest that experimental steroid fever in man may be mediated by an endogenous pyrogen released from leukocytes.
PMCID: PMC297152  PMID: 16695933
4.  Recurrent fever of unknown etiology: failure to demonstrate association between fever and plasma unconjugated etiocholanolone 
Journal of Clinical Investigation  1969;48(3):558-563.
A sensitive method for determination of plasma unconjugated etiocholanolone by double-isotope-derivative dilution has been described. The mean values for normal subjects was 0.038±0.003 (SEM) μg/100 ml.
40 patients, 20 with familial Mediterranean fever and 20 with other diseases characterized by recurrent fever were studied. The over-all mean concentration of plasma unconjugated etiocholanolone for the patients (febrile or afebrile) was 0.101 ±0.012 μg/100 ml, significantly above that of normals. Mean plasma values for the patients while they were febrile did not differ from the mean values when they were afebrile. It is suggested that the concentration of plasma unconjugated etiocholanolone is not related to fever in these patients.
PMCID: PMC535721  PMID: 4886315
5.  Anticonvulsant Potencies of the Enantiomers of the Neurosteroids Androsterone and Etiocholanolone Exceed those of the Natural Forms 
Psychopharmacology  2014;231(17):3325-3332.
Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms.
The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models.
Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ).
In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor positive allosteric modulators are generally weak in the MES test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α- A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h).
The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
PMCID: PMC4134984  PMID: 24705905
androsterone; etiocholanolone; enantiomer; 6-Hz test; pentylenetetrazol test; maximal electroshock test
6.  Heterogeneity of human serum amyloid A proteins 
Serum amyloid A proteins (SAA), presumed precursors of the tissue amyloid A proteins (AA) characteristic of secondary amyloidosis, have been isolated from the plasma high-density lipoproteins (HDL) of normals after etiocholanolone-induced inflammation and from patients with Wegener's granulomatosis, systemic lupus erythematosis, juvenile rheumatoid arthritis, Waldenstrom's macroglobulinemia, and Goodpasture's syndrome. At least six polymorphic forms of SAA wer identified among the low molecular weight proteins of HDL, and these comprosed up to 27% of the total HDL protein. Gel and ion-exchange chromatography permitted isolation of the SAA polymorphs in homogeneous form. Their amino acid compositions were very similar, they were indistinguishable in cationic and sodium dodecyl sulfate-polyacrylamide gel electrophoresis systems, and each had the terminal sequency COOH- Tyr-Lys-Phe-. Charge heterogeneity in anionic-urea polyacrylamide gel electropherograms was unaffected by neuaminidase treatment, and none of the SAA protein bands stained with the periodate-Schiff reagent. The two major SAA polymorphs, designated SAA4 and SAA5 according to their order of elution from DEAE-cellulose, had different NH2-terminal sequences. Manual Edman degradation demonstrated NH2-arg-ser-phe-phe- for SAA4 and NH2-ser-phe-phe- for SAA5. This NH2-terminal heterogeneity corresponds to that most frequently reported for AA and suggests that microheterogeneity in SAA may underlie that already documented in AA. Sufficient quantitites of the other SAA polymorphs were not available for similar analyses, but the amino acid compositions do not indicate that NH2-terminal heterogeneity accounts for all of the observed polymorphism. Artifactual polymorphism also appears unlikely, and the heterogeneiy of SAA may reflect origin from more than one cell type with or without posttranslational modificaton. We calculate from quantitative COOH-terminal analyses that SAA is of 11,000-11,900 mol wt. Primary structure studies have shown AA t be a single chain protein of 76 residues, and SAA, therefore, appears to contain a peptide of 33 amino acids that is missing from AA.
PMCID: PMC2185911  PMID: 6774048
7.  The Interaction between Steroid Hormones and Lipid Monolayers on Water 
The Journal of General Physiology  1971;58(6):650-666.
The interaction of progesterone, testosterone, androsterone, and etiocholanolone with insoluble lipid films (cholesterol and saturated hydrocarbons containing either alcohol, ester, acetamide, phosphate, amine, or carboxyl groups) was studied. In addition to surface pressure and surface potential measurements of the surface films, radioactive tracers were used to measure the concentration of adsorbed steroid in the lipid films. In general, steroids form mixed films with the insoluble lipid films. Compression of the insoluble lipid films to their most condensed state leads to complete ejection of adsorbed steroid from the surface in all cases except with the amine, for which a small amount of steroid is still retained in the surface. Interactions between the steroids and insoluble lipids are primarily due to van der Waals or dispersion forces; there were no significant contributions from dipole-dipole interactions (except possibly with the amine). Specific interactions between cholesterol and the soluble steroids were not observed. Evidence suggests that low steroid concentrations influence structure of lipid films by altering the hydration layer in the surface film. In contrast to a specific site of action, it is proposed that steroid hormones initiate structural changes in a variety of biological sites; this model of steroid action is consistent with the ubiquity of many steroid hormones.
PMCID: PMC2226044  PMID: 5120392
8.  Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone. 
Journal of Clinical Investigation  1975;56(4):808-813.
To study the potential application of glucocorticosteroid administration for the measurement of the bone marrow neutrophil reserve response, blood neutrophil count changes were measured in normal subjects after the administration of intravenous hydrocortisone (25, 50, 100, 200, and 400 mg) and oral prednisone (5, 10, 20, 40, and 80 mg). The upper three doses of both steroids increased the blood neutrophil count by approximately 4,000 cells/mm3. The neutrophilia occurring after hydrocortisone (200 mg) and/or prednisone (40 mg) was compared with that observed after endotoxin (0.8 ng/kg) and etiocholanolone (0.1 mg/kg) in 14 normal subjects, 7 patients with Wegener's granulomatosis on cyclophosphamide therapy and 10 patients with chronic idiopathic neutropenia. The normal responses (mean increase of blood neutrophils/mm3 above base line +/- 1 SEM) were: hydrocortisone 4,220 +/- 320, prednisone 4,610 +/- 360, endotoxin 6,060 +/- 880, and etiocholanolone 3,780 +/- 440. In the patient studies, etiocholanolone gave the smallest mean responses, but, in general, the results were similar for all agents. These data indicate that these glucocorticosteroids can be used as equivalent agents to endotoxin and etiocholanolone for measuring the neutrophil reserve response.
PMCID: PMC301935  PMID: 1159089
9.  Serum metabolomic profile and potential biomarkers for severity of fibrosis in nonalcoholic fatty liver disease 
Journal of Gastroenterology  2013;48(12):1392-1400.
Biomarker for usefulness in diagnosing advanced fibrosis in nonalcoholic fatty liver disease (NAFLD) is expected. In order to discover novel biomarkers for NAFLD and its pathogenesis, we performed matabolomics screening.
(1) The initial cohort was 44 NAFLD patients. (2) This validation cohort was 105 NAFLD patients, 26 primary biliary cirrhosis (PBC) patients, and 48 healthy controls. Using capillary electrophoresis and liquid chromatography with mass spectrometry, we analyzed low molecular weight metabolites in these groups.
1. In the initial cohort, we found 28 metabolites associated with advanced fibrosis. Among them, 4 sulfated steroids showed the greatest difference. A decrease of dehydroepiandrosterone sulfate (DHEA-S) and 5α-androstan-3β ol-17-one sulfate (etiocholanolone-S) was observed with the progression of fibrosis. Furthermore, 16 hydroxydehydroepiandrosterone sulfate (16-OH-DHEA-S) increased with the progression of fibrosis. 2. In the validation cohort, the decrease of DHEA-S and etiocholanolone-S, as well as the increase of 16-OH-DHEA-S, with the progression of fibrosis was confirmed. The 16-OH-DHEA-S/DHEA-S ratio and 16-OH-DHEA-S/etiocholanolone-S ratio were even more strongly associated with the grade of fibrosis. Among PBC patients, 16-OH-DHEA-S tended to be higher in stages 3 and 4 than in stages 1 and 2. However, levels of DHEA-S, etiocholanolone-S, and the two ratios were not associated with the stage of PBC.
Several metabolic products were found to be biomarkers of fibrosis in NAFLD and could also be useful for diagnosis of this condition. Our findings suggested disturbance of hormone metabolism in NAFLD and might lead to the development of new therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-013-0766-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3889284  PMID: 23478936
10.  Multiyear Climate Variability and Dengue—El Niño Southern Oscillation, Weather, and Dengue Incidence in Puerto Rico, Mexico, and Thailand: A Longitudinal Data Analysis 
PLoS Medicine  2009;6(11):e1000168.
Michael Johansson and colleagues use wavelet analysis to show that there is limited evidence for a multiyear relationship between climate and dengue incidence in Puerto Rico, Mexico, and Thailand.
The mosquito-borne dengue viruses are a major public health problem throughout the tropical and subtropical regions of the world. Changes in temperature and precipitation have well-defined roles in the transmission cycle and may thus play a role in changing incidence levels. The El Niño Southern Oscillation (ENSO) is a multiyear climate driver of local temperature and precipitation worldwide. Previous studies have reported varying degrees of association between ENSO and dengue incidence.
Methods and Findings
We analyzed the relationship between ENSO, local weather, and dengue incidence in Puerto Rico, Mexico, and Thailand using wavelet analysis to identify time- and frequency-specific association. In Puerto Rico, ENSO was transiently associated with temperature and dengue incidence on multiyear scales. However, only local precipitation and not temperature was associated with dengue on multiyear scales. In Thailand, ENSO was associated with both temperature and precipitation. Although precipitation was associated with dengue incidence, the association was nonstationary and likely spurious. In Mexico, no association between any of the variables was observed on the multiyear scale.
The evidence for a relationship between ENSO, climate, and dengue incidence presented here is weak. While multiyear climate variability may play a role in endemic interannual dengue dynamics, we did not find evidence of a strong, consistent relationship in any of the study areas. The role of ENSO may be obscured by local climate heterogeneity, insufficient data, randomly coincident outbreaks, and other, potentially stronger, intrinsic factors regulating transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, as many as 50–100 million people become infected with one of four closely related dengue viruses through the bite of a female Aedes aegypti mosquito that has acquired the virus by feeding on infected human blood. Dengue is endemic (always present) in many tropical and subtropical countries but its incidence (the number of new cases in a population over a given time period) follows a seasonal pattern. This is because the abundance of Ae. aegypti is regulated by rainfall, which provides breeding sites and stimulates egg hatching, and by temperature, which influences the insects' survival and their rate of development and reproduction. Temperature also affects the mosquitoes' ability to transmit dengue virus—higher temperatures increase transmission rates. Although some people who become infected with dengue have no symptoms, many develop dengue fever, a severe, flu-like illness that lasts a few days. Other people—more than half a million a year—develop dengue hemorrhagic fever, a potentially fatal condition. There is no vaccine to prevent dengue and no specific treatment for the disease, but standard medical care can prevent most deaths from dengue.
Why Was This Study Done?
As well as seasonal variations in the incidence of dengue, large dengue outbreaks (epidemics) occur every few years. To help with health care planning, public health officials would like a way to predict when these epidemics are likely to occur, but to develop such a system requires a good understanding of the factors that lead to major epidemics. Although variations in host–virus interactions (for example, changes in host immunity to dengue) almost certainly play an important role in the timing of dengue epidemics, interannual changes in temperature and rainfall could also be involved. One major cause of global interannual weather variation is the El Niño Southern Oscillation (ENSO), a climate cycle centered on the Pacific Ocean that repeats every 3–4 years. Previous studies have reported varying degrees of association between ENSO and dengue. In this study, the researchers reanalyze the relationship between ENSO, local weather, and dengue incidence in three dengue-endemic countries using “wavelet analysis.” This mathematical technique can separate the effects of seasonal weather variations on dengue incidence from those of interannual weather fluctuations.
What Did the Researchers Do and Find?
The researchers retrieved data on the incidence of dengue fever and dengue hemorrhagic fever in Puerto Rico, Thailand and Mexico since the mid 1980s from national surveillance systems. They also collected historical weather data for each country and information on ENSO. They then used these data and wavelet analysis to investigate the relationship between ENSO, local weather, and dengue incidence in each country on the annual scale and on the multiyear scale. On the annual scale, temperature, rainfall, and dengue incidence were strongly associated in all three countries. On the multiyear scale, ENSO was associated with temperature and with dengue incidence in Puerto Rico, but only for part of the study period. Only local rainfall was associated with the incidence of dengue in that country. The lack of a direct path of association from ENSO to either weather variable to dengue incidence suggests that the ENSO–dengue association may be a spurious result. In Thailand, ENSO was associated with both temperature and rainfall, and rainfall was associated with dengue incidence. However, detailed analysis suggests that this latter association was also probably spurious. Finally, there was no association between any of the variables in Mexico on the multiyear scale.
What Do These Findings Mean?
Although these findings show a strong associations between both temperature and rainfall and dengue incidence on the annual scale in Puerto Rico, Thailand, and Mexico, they provide little evidence for any relationship between ENSO, climate, and dengue incidence. Multiyear climate variability may play a role in interannual variations in dengue incidence, the researchers suggest, but their study does not provide any evidence for a strong and consistent relationship between climate variability and dengue incidence. It is possible that the effects of ENSO on dengue incidence are being masked by local variations in weather or by stronger factors regulating disease transmission such as host–virus or host–vector interactions. Future studies into the relationship between dengue outbreaks and multiyear climate variability will need to include these and other factors. For now, however, information on ENSO cannot be used to design an early warning system for dengue outbreaks.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Pejman Rohani
The US Centers for Disease Control and Prevention provides detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information on dengue fever and dengue hemorrhagic fever around the world (in several languages)
Links to additional resources about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has pages on the El Nio Southern Oscillation and on wavelet analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2771282  PMID: 19918363
11.  Glucuronidation of the steroid enantiomers ent-17β-estradiol, ent-androsterone and ent-etiocholanolone by the human UDP-glucuronosyltransferases 
Steroids enantiomers are interesting compounds for detailed exploration of drug metabolizing enzymes, such as the UDP-glucuronosyltransferases (UGTs). We have now studied the glucuronidation of the enantiomers of estradiol, androsterone and etiocholanolone by the 19 human UGTs of subfamilies 1A, 2A and 2B. The results reveal that the pattern of human UGTs of subfamily 2B that glucuronidate ent-17β-estradiol, particularly 2B15 and 2B17, resembles the glucuronidation of epiestradiol (17α-estradiol) rather than 17β-estradiol, the main physiological estrogen. The UGTs of subfamilies 1A and 2A exhibit higher degree of regioselectivity than enantioselectivity in the conjugation of these estradiols, regardless of whether the activity is primarily toward the non-chiral site, 3-OH (UGT1A1, UGT1A3, UGT1A7, UGT1A8 and, above all, UGT1A10), or the 17-OH (UGT1A4). In the cases of etiocholanolone and androsterone, glucuronidation of the ent-androgens, like the conjugation of the natural androgens, is mainly catalyzed by UGTs of subfamilies 2A and 2B. Nevertheless, the glucuronidation of ent-etiocholanolone and ent-androsterone by both UGT2B7 and UGT2B17 differ considerably from their respective activity toward the corresponding endogenous androgens, whereas UGT2A1-catalyzed conjugation is much less affected by the stereochemistry differences. Kinetic analyses reveal that the Km value of UGT2A1 for ent-estradiol is much higher than the corresponding value in the other two high activity enzymes, UGT1A10 and UGT2B7. Taken together, the results highlight large enantioselectivity differences between individual UGTs, particularly those of subfamily 2B.
PMCID: PMC3234363  PMID: 21899827
Certain factors of climate are favorable to streptococcus respiratory diseases. In those tropical environments where hemolytic streptococcus is unusual in the throat flora, scarlet fever is unknown and rheumatic fever rare. In New York City, however, following epidemic waves of pharyngitis with hemolytic streptococcus the incidence of rheumatic fever rises precipitously. The correlation between the geographical distribution of hemolytic streptococcus and rheumatic fever is a definite one. Furthermore, in New York City during the seasons of the year in which hemolytic streptococcus is seldom recovered from the pharynx, acute attacks of rheumatism are unusual. Corresponding to the seasonal rise in hemolytic streptococcus infections, the curve of incidence of acute rheumatism shows a similar form. Among the children of wealthy patients, enjoying great protection, hemolytic streptococcus has been recovered infrequently from the throat, and rheumatism has not been encountered during this study. Among the poor under observation in New York City, however, the organism is found frequently in the pharyngeal flora, and rheumatic fever is common. The findings suggest that poverty and unhygienic living conditions favor both the activity of hemolytic streptococcus in the throat and the incidence of rheumatic fever. Moreover, localized outbreaks of rheumatism have been observed frequently following epidemics of "sore throat". Bacteriological studies of these upper respiratory infections demonstrate a close relationship between the advent of hemolytic streptococcus in the throat flora and the outbreak of rheumatic fever in susceptible individuals. In addition to these studies of streptococcus infections and their relationship to the development of rheumatic fever, observations of the rheumatic patient add further emphasis to this association. First, among a group of rheumatic children in an isolated environment, reactivation of the rheumatic process has been recognized only following the advent of hemolytic streptococcus in the throat flora. Also, an investigation of families in which several members have rheumatic heart disease has led to the same conclusion. Recrudescences of the disease have been observed under a variety of conditions among these individuals. However, the one constant factor in the outbreaks of recrudescences in rheumatic homes is their association with family epidemics of hemolytic streptococcus infection. Moreover, by studying rheumatic patients before, during and after transplantation to a tropical environment, it has been possible to demonstrate a close relationship between activity of the disease process and infection with hemolytic streptococcus. While the rheumatic patients remained in the tropics this organism was not recovered from the pharyngeal flora, and the disease process seemed quiescent. On return to New York City, those individuals who have escaped respiratory infection have remained symptom-free. However, of those who have contracted hemolytic streptococcus pharyngitis, each has developed a rheumatic attack within 3 weeks after infection. Finally, extensive bacteriological studies made in ambulatory rheumatic subjects over a period of 4 years have demonstrated that the individuals who escape respiratory disease remain free of rheumatic manifestations. On the other hand, the majority of rheumatic patients who contract hemolytic streptococcus pharyngitis experience shortly afterward a definite recrudescence of their disease. In conclusion, there is a close relationship between respiratory infection with hemolytic streptococcus and activity of the rheumatic process in susceptible individuals.
PMCID: PMC2132196  PMID: 19870089
From Fig. 1 it may be seen that the effect of elevated temperature during the pyrexial period upon 1/K and therefore on the dissociation curve of oxyhemoglobin was, on the average, greater than would have been expected from experiments on normal blood in vitro, and greater than would be expected in view of the alkalosis occurring See PDF for Structure during fever. Temperature rise, and excess hydroxyl ion acting in vitro in the opposite directions, seemed to indicate a more stable state of affairs than was found. Apparently other factors have come into play, as, for example, alterations in the proportions and concentrations of the various electrolytes. In pneumonia, for instance, there is a retention of chloride during the febrile period with excessive loss of phosphates. The variations were not due to variations in the hemoglobin molecule itself since from the work of Adair, Barcroft, and Bock (18) hemoglobin must apparently be reckoned as having identical properties in normal individuals of the same species. If Barcroft's (19) hypothesis be right, namely that the CH within the corpuscle is higher than that of the plasma, the observed variations of 1/K may not be so surprising. In view of the fact that the hemoglobin inside the corpuscle is enclosed within a semipermeable membrane, the possibility arises of the setting up of membrane equilibria which will protect the respiratory pigment from excessive changes of reaction that may occur in the plasma, and thus the optimum conditions for the carriage of oxygen to the tissues may be maintained. Krogh and Leitch (10) in 1919 also drew attention to the protected situation of hemoglobin inside the corpuscle. In Case 6 it seems as if the alkalosis consequent on the febrile state had gained the upper hand and had extinguished the normal temperature reaction. This is rather confirmed by the fact that clinically the case showed one of the earlier signs of an alkalosis; namely, twitching of the facial muscles. Case 10, who had been on salicylate, also showed an analogous effect, when 6 days after the first observation the temperature shift was practically nil. The relationship between pH, 1/K, and the febrile temperature still awaits investigation. The extent of the shift of the dissociation curve was not by any means uniform; in neither Fig. 1 nor Fig. 2 is the highest value of 1/K at the highest temperature recorded. Fig. 2 shows the effect of temperature rise upon 1/K after cessation of the pyrexia; the effect is not so marked. Some cases, however, showed a variation in excess of the normal as if there was not yet complete return to normal. See PDF for Structure Biologically these changes are of importance in that this shifting of the dissociation curve to the right in fever means that there is more oxygen available for the tissues than normally, more especially at higher pressures. The tension of unloading is raised. This, in addition to the accelerated circulation and the probable increased velocity o[ reaction, means that even in a localized area of inflammation, if there is increased temperature, the tissues are placed in a better position for resisting infection as a result of their better oxygenation. That there is increased metabolism during fever has been conclusively shown by Du Bois (20) and others using large bed calorimeters. Du Bois has shown that the increase in metabolism obeys van't Hoff's law, increasing 13 per cent for each 1°C. rise. This shifting of the curve then falls into line with these observations as an adaptive response to the febrile condition, and the febrile temperature, if not too great, would seem to be a purposive attempt to aid the combating of infection. This shifting of the curve probably explains Uyeno's (21) observation on the effect of increased temperature on the circulation in the cat; namely, increased coefficient of utilization, and increased fall in the saturation of the mixed venous blood. Turning now to Table II, we find that, if the CO2 dissociation curve of Haldane (12) is accepted as normal, the bicarbonate reserve of five of the cases was above normal, of one normal, and of the rest below normal. Gastric secretion was not the cause of the varying curves, since the time of drawing the blood in all cases was during intestinal digestion. No observations having been made on the blood pH or the alveolar CO2, we cannot be absolutely certain as to the actual reactions, more especially in the last cases; Case 6, however, was probably one showing a partially compensated CO2 deficit in view of the absolute lowering of the total bicarbonate and evidence clinically of a tendency to alkalosis. Case 3, which had a lowered reserve, was probably similar. Koehler (22) gives a series of blood pH determinations in acute fevers in which ten out of twelve cases showed an uncompensated alkalosis when the temperature was 103°F. (39.4°C.) or over. Pemberton and Crouter (23) in a study on the response to the therapeutic application of external heat also observed a tendency for the reaction to shift to the alkaline side as shown by the alteration in the pH of the sweat. Hill and Flack (24) and Bazett and Haldane (25) observed that in thermal fever there was an excessive loss of CO2 comparable to the effect of hyperpnea. These facts are of importance in view of the above results regarding the bicarbonate reserve. That there was a definite alkalosis in some of the cases is at least shown by the value of 1/K at 37.0°C. during the pyrexial period in Cases 1, 2, and 7. The upper limits of 1/K at 37.0°C. both during pyrexia and after were similar. Of other factors that might be considered, reference may be made to the work of Barbour and his associates (26–29), who showed that in hyperthermia and fever there is an alteration in the concentration of the blood. But the changes were hardly of such magnitude as to cause the variations above detailed.
PMCID: PMC2130946  PMID: 19868990
The question of the relationship of streptococci to the etiology of infectious arthritis and of rheumatic fever is of the utmost importance. If a streptococcus or group of streptococci could be shown to be associated See PDF for Structure with either disease, some form of specific treatment might be available. The possibility of primary streptococcic infection as the cause of rheumatic fever, and, to a less extent, of acute infectious arthritis would seem to be a reasonable conjecture because of the frequency of associated throat, sinus or other focal infection. To consider that these same streptococci remain in or about the affected joint and to such an extent that they are found in the blood stream in cases of chronic infectious arthritis of years' duration demands a rather unique conception. Recent investigative work has certainly tended to confirm the importance of streptococci in these diseases, but, if all the published reports are considered as a group, one can not help being impressed with the inconsistency and peculiarities of the findings. In blood cultures from cases of rheumatic fever Clawson (7) recovered Streptococcus viridans, Small (8) and Birkhaug (9) non-hemolytic (gamma type) streptococci, and Cecil et al. (3) Streptococcus viridans, rarely hemolytic and non-hemolytic streptococci. In blood cultures from cases of infectious arthritis Cecil et al. (2) recovered attenuated hemolytic streptococci and occasionally Streptococcus viridans, non-hemolytic streptococci and diphtheroids and Margolis and Dorsey (10) green-producing and indifferent streptococci and diphtheroids, whereas from synovial fluids and regional lymph nodes Forkner, Shands and Poston (4) and Poston (5) obtained Streptococcus viridans and Margolis and Dorsey (11) recovered green-producing and indifferent streptococci and diphtheroids from epiphyseal marrows, bones and synovial membranes. On the other hand, Jordan (12) and Nye and Seegal (13) and the work reported in this paper have failed to confirm these findings. If a streptococcus is the infective agent, it is difficult to explain why the organisms recovered so consistently by certain groups of investigators are so different and why the findings of other groups are entirely negative. The chances of contamination, even with the most careful manipulation, are extremely favorable when using a cultural technique which demands subculturing a fluid medium every 3 to 5 days for a period of 4 to 6 weeks. The question arises as to what organisms should be considered as contaminants. Cultures found to contain Staphylococcus albus have never been judged significant. Margolis and Dorsey (11) have excluded Gram-positive bacilli from their series, but have included diphtheroids. Cecil et al. (2) reported the recovery of diphtheroids and Micrococcus zymogenes from blood cultures which they did not consider contaminated. Jordan (12) recovered short Gram-negative bacilli and Gram-positive bacilli and questioned their importance. The occurrence of such bacteria would appear to be not unlike that of the non-hemolytic (gamma type) streptococci reported by Small (7), Birkhaug (9) and, rarely, by Cecil et al. (2) and Margolis and Dorsey (10,11). In the work reported in this paper and in previously published work (13) with blood cultures from cases of rheumatic fever, staphylococci, Gram-positive bacilli and diplococci and diphtheroids have been isolated from a certain number of the cultures. Since these were found, as a rule, in only 1 of 2 or more cultures from the same blood and since such organisms occurred about as frequently in cultures from control cases, they have been considered merely contaminants. The findings in the 9 cases of arthritis with positive blood cultures reported by Margolis and Dorsey (10) are certainly far from convincing. These authors found green-producing streptococci in 5 of the 9 cases, but duplicate cultures on the same blood, with one exception, were always negative and the two repeat cultures were negative. Furthermore, in the 3 cases yielding indifferent streptococci in one subculture all subsequent subcultures were negative. In the work reported in this paper a green-producing and a non-hemolytic streptococcus were isolated from blood cultures, but a Gram-positive diplococcus and a Gram-positive bacillus, respectively, were recovered from the same cultures. A consideration of the above would seem to point to the probability, even certainty, of streptococci occurring in some cultures as contaminants; and the work of Olitsky and Long (14) and Long, Olitsky and Stewart (15) has clearly demonstrated that the air contamination of cultures of ground material with non-hemolytic green-producing streptococci can occur just as easily as with diphtheroids and staphylococci. It is obvious, in such cases, that the types of organisms recovered are dependent on the flora of the air of the laboratory or of the throat of the laboratory worker, and this point may well explain the differences in the cultural findings under consideration. A number of years ago numerous articles (16–19) appeared relative to the bacteriologic flora of lymph nodes, particularly those from cases of Hodgkin's disease, and it is interesting to note that the organisms recovered were quite similar to those which have been recovered from the blood and tissues of cases of arthritis and rheumatic fever, with the exception that the diphtheroids were, at that time, much more in prominence. Regardless of elaborate serological studies and animal experiments, streptococci must be recovered consistently by several groups of laboratory workers before their etiologic rôle in chronic arthritis and rheumatic fever can be accepted. Duplicate cultures and repeat cultures should yield the same organism in a generous percentage of cases and cultures from cases of other diseases or from normal persons should be negative. Positive cultures from duplicate cultures opened only at the time when the first culture showed growth would make the findings more significant than if the whole series were subcultured every 3 to 5 days. The work of Cecil, Nicholls and Stainsby on the bacteriology of the blood and joints in chronic arthritis and rheumatic fever has apparently been carried out most carefully and thoroughly and their results are very consistent and convincing. In spite of attempts to follow their methods in the selection of patients and in cultural technique, the results on the relatively small series of cases which are reported here fail to confirm their findings.
PMCID: PMC2131922  PMID: 19869811
15.  Role of prostaglandin E in the biphasic fever response to endotoxin 
The Journal of Experimental Medicine  1981;154(4):1212-1224.
Biphasic fevers were induced in sheep with intravascular infusions or injections of 4-10 μg (80-200 ng/kg) of endotoxin, whereas monophasic fevers were obtained with doses of 1-2/μg (20-40 ng/kg). A marked increase in arterial blood pressure invariably accompanied the onset of fever; the latency of responses to the higher and lower doses of endotoxins averaged 26 min and 42 min, respectively. Prostaglandin (PG) assays of plasma from the carotid artery and jugular vein during fever episodes revealed a surge of PGE and PGF coincident with the pressor response and the first phase of fever, but PG were not detected in plasma samples taken throughout the second phase of fever. PG measurements of arterial and venous plasma collected at a distal site (hind limb) showed a similar surge of PGE and PGF in association with the early fever response, indicating that intravascular PG synthesis and release represents a generalized systemic response to circulating endotoxin. Carotid arterial infusions of PGE(2) produced immediate monophasic fevers and pressor responses, whereas PGD(2) infusions produced an immediate pressor effect but no fever. Infusions of PGF(2α) or prostacyclin, however, evoked neither fever nor pressor effects. Intracarotid infusions of leukocyte pyrogen (LP) caused monophasic fevers with latent periods of 15-20 min but pressor responses were not seen and neither PGE nor PGF were detected in plasma samples from the carotid artery or jugular vein before or during fever. Indomethacin, a potent inhibitor of arachidonic acid metabolism, blocked fever responses to endotoxin and to LP. These findings implicate PGE as the mediator of the early phase of endotoxin fever and imply a role for another pyrogenic metabolite ofarachidonic acid in the mediation of the second phase of fever, i.e., the phase associated with circulating LP. It is possible that both pyrogenic metabolites are generated within the vascular compartment, reaching thermoregulatory centers of the brain by transfer across the blood-brain interface.
PMCID: PMC2186491  PMID: 7288365
16.  Monitoring the Impact of Influenza by Age: Emergency Department Fever and Respiratory Complaint Surveillance in New York City 
PLoS Medicine  2007;4(8):e247.
The importance of understanding age when estimating the impact of influenza on hospitalizations and deaths has been well described, yet existing surveillance systems have not made adequate use of age-specific data. Monitoring influenza-related morbidity using electronic health data may provide timely and detailed insight into the age-specific course, impact and epidemiology of seasonal drift and reassortment epidemic viruses. The purpose of this study was to evaluate the use of emergency department (ED) chief complaint data for measuring influenza-attributable morbidity by age and by predominant circulating virus.
Methods and Findings
We analyzed electronically reported ED fever and respiratory chief complaint and viral surveillance data in New York City (NYC) during the 2001–2002 through 2005–2006 influenza seasons, and inferred dominant circulating viruses from national surveillance reports. We estimated influenza-attributable impact as observed visits in excess of a model-predicted baseline during influenza periods, and epidemic timing by threshold and cross correlation. We found excess fever and respiratory ED visits occurred predominantly among school-aged children (8.5 excess ED visits per 1,000 children aged 5–17 y) with little or no impact on adults during the early-2002 B/Victoria-lineage epidemic; increased fever and respiratory ED visits among children younger than 5 y during respiratory syncytial virus-predominant periods preceding epidemic influenza; and excess ED visits across all ages during the 2003–2004 (9.2 excess visits per 1,000 population) and 2004–2005 (5.2 excess visits per 1,000 population) A/H3N2 Fujian-lineage epidemics, with the relative impact shifted within and between seasons from younger to older ages. During each influenza epidemic period in the study, ED visits were increased among school-aged children, and each epidemic peaked among school-aged children before other impacted age groups.
Influenza-related morbidity in NYC was highly age- and strain-specific. The impact of reemerging B/Victoria-lineage influenza was focused primarily on school-aged children born since the virus was last widespread in the US, while epidemic A/Fujian-lineage influenza affected all age groups, consistent with a novel antigenic variant. The correspondence between predominant circulating viruses and excess ED visits, hospitalizations, and deaths shows that excess fever and respiratory ED visits provide a reliable surrogate measure of incident influenza-attributable morbidity. The highly age-specific impact of influenza by subtype and strain suggests that greater age detail be incorporated into ongoing surveillance. Influenza morbidity surveillance using electronic data currently available in many jurisdictions can provide timely and representative information about the age-specific epidemiology of circulating influenza viruses.
Don Olson and colleagues report that influenza-related morbidity in NYC from 2001 to 2006 was highly age- and strain-specific and conclude that surveillance using electronic data can provide timely and representative information about the epidemiology of circulating influenza viruses.
Editors' Summary
Seasonal outbreaks (epidemics) of influenza (a viral infection of the nose, throat, and airways) send millions of people to their beds every winter. Most recover quickly, but flu epidemics often disrupt daily life and can cause many deaths. Seasonal epidemics occur because influenza viruses continually make small changes to the viral proteins (antigens) that the human immune system recognizes. Consequently, an immune response that combats influenza one year may provide partial or no protection the following year. Occasionally, an influenza virus with large antigenic changes emerges that triggers an influenza pandemic, or global epidemic. To help prepare for both seasonal epidemics and pandemics, public-health officials monitor influenza-related illness and death, investigate unusual outbreaks of respiratory diseases, and characterize circulating strains of the influenza virus. While traditional influenza-related illness surveillance systems rely on relatively slow voluntary clinician reporting of cases with influenza-like illness symptoms, some jurisdictions have also started to use “syndromic” surveillance systems. These use electronic health-related data rather than clinical impression to track illness in the community. For example, increased visits to emergency departments for fever or respiratory (breathing) problems can provide an early warning of an influenza outbreak.
Why Was This Study Done?
Rapid illness surveillance systems have been shown to detect flu outbreaks earlier than is possible through monitoring deaths from pneumonia or influenza. Increases in visits to emergency departments by children for fever or respiratory problems can provide an even earlier indicator. Researchers have not previously examined in detail how fever and respiratory problems by age group correlate with the predominant circulating respiratory viruses. Knowing details like this would help public-health officials detect and respond to influenza epidemics and pandemics. In this study, the researchers have used data collected between 2001 and 2006 in New York City emergency departments to investigate these aspects of syndromic surveillance for influenza.
What Did the Researchers Do and Find?
The researchers analyzed emergency department visits categorized broadly into a fever and respiratory syndrome (which provides an estimate of the total visits attributable to influenza) or more narrowly into an influenza-like illness syndrome (which specifically indicates fever with cough and/or sore throat) with laboratory-confirmed influenza surveillance data. They found that emergency department visits were highest during peak influenza periods, and that the affect on different age groups varied depending on the predominant circulating viruses. In early 2002, an epidemic reemergence of B/Victoria-lineage influenza viruses caused increased visits among school-aged children, while adult visits did not increase. By contrast, during the 2003–2004 season, when the predominant virus was an A/H3N2 Fujian-lineage influenza virus, excess visits occurred in all age groups, though the relative increase was greatest and earliest among school-aged children. During periods of documented respiratory syncytial virus (RSV) circulation, increases in fever and respiratory emergency department visits occurred in children under five years of age regardless of influenza circulation. Finally, the researchers found that excess visits to emergency departments for fever and respiratory symptoms preceded deaths from pneumonia or influenza by about two weeks.
What Do These Findings Mean?
These findings indicate that excess emergency department visits for fever and respiratory symptoms can provide a reliable and timely surrogate measure of illness due to influenza. They also provide new insights into how different influenza viruses affect people of different ages and how the timing and progression of each influenza season differs. These results, based on data collected over only five years in one city, might not be generalizable to other settings or years, warn the researchers. However, the present results strongly suggest that the routine monitoring of influenza might be improved by using electronic health-related data, such as emergency department visit data, and by examining it specifically by age group. Furthermore, by showing that school-aged children can be the first people to be affected by seasonal influenza, these results highlight the important role this age group plays in community-wide transmission of influenza, an observation that could influence the implementation of public-health strategies such as vaccination that aim to protect communities during influenza epidemics and pandemics.
Additional Information.
Please access these Web sites via the online version of this summary at
• US Centers for Disease Control and Prevention provides information on influenza for patients and health professionals and on influenza surveillance in the US (in English, Spanish, and several other languages)
• World Health Organization has a fact sheet on influenza and on global surveillance for influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
• The MedlinePlus encyclopedia contains a page on flu (in English and Spanish)
• US National Institute of Allergy and Infectious Diseases has a feature called “focus on flu”
• A detailed report from the US Centers for Disease Control and Prevention titled “Framework for Evaluating Public Health Surveillance Systems for Early Detection of Outbreaks” includes a simple description of syndromic surveillance
• The International Society for Disease Surveillance has a collaborative syndromic surveillance public wiki
• The Anthropology of the Contemporary Research Collaboratory includes working papers and discussions by cultural anthropologists studying modern vital systems security and syndromic surveillance
PMCID: PMC1939858  PMID: 17683196
17.  Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data 
PLoS Medicine  2014;11(5):e1001638.
Neil Ferguson and colleagues estimate the disease burden of yellow fever in Africa, as well as the impact of mass vaccination campaigns.
Please see later in the article for the Editors' Summary
Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.
Methods and Findings
Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.
The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000–380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000–180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%–31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys.
With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.
Please see later in the article for the Editors' Summary
Editors' Summary
Yellow fever is a flavivirus infection that is transmitted to people and to non-human primates through the bites of infected mosquitoes. This serious viral disease affects people living in and visiting tropical regions of Africa and Central and South America. In rural areas next to forests, the virus typically causes sporadic cases or even small-scale epidemics (outbreaks) but, if it is introduced into urban areas, it can cause large explosive epidemics that are hard to control. Although many people who contract yellow fever do not develop any symptoms, some have mild flu-like symptoms, and others develop a high fever with jaundice (yellowing of the skin and eyes) or hemorrhaging (bleeding) from the mouth, nose, eyes, or stomach. Half of patients who develop these severe symptoms die. Because of this wide spectrum of symptoms, which overlap with those of other tropical diseases, it is hard to diagnose yellow fever from symptoms alone. However, serological tests that detect antibodies to the virus in the blood can help in diagnosis. There is no specific antiviral treatment for yellow fever but its symptoms can be treated.
Why Was This Study Done?
Eradication of yellow fever is not feasible because of the wildlife reservoir for the virus but there is a safe, affordable, and highly effective vaccine against the disease. Large-scale vaccination efforts during the 1940s, 1950s, and 1960s reduced the yellow fever burden for several decades but, after a period of low vaccination coverage, the number of cases rebounded. In 2005, the Yellow Fever Initiative—a collaboration between the World Health Organization (WHO) and the United Nations Children Fund supported by the Global Alliance for Vaccines and Immunization (GAVI Alliance)—was launched to create a vaccine stockpile for use in epidemics and to implement preventive mass vaccination campaigns in the 12 most affected countries in West Africa. Campaigns have now been implemented in all these countries except Nigeria. However, without an estimate of the current yellow fever burden, it is hard to determine the impact of these campaigns. Here, the researchers use recent yellow fever occurrence data, serological survey data, and improved estimation methods to update estimates of the yellow fever burden and to determine the impact of mass vaccination on this burden.
What Did the Researchers Do and Find?
The researchers developed a generalized linear statistical model and used data on the locations where yellow fever was reported between 1987 and 2011 in Africa, force of infection estimates for a limited set of locations where serological surveys were available (the force of infection is the rate at which susceptible individuals acquire a disease), data on vaccination coverage, and demographic and environmental data for their calculations. They estimate that about 130,000 yellow fever cases with fever and jaundice or hemorrhage occurred in Africa in 2013 and that about 78,000 people died from the disease. By evaluating the difference between this estimate, which takes into account the current vaccination coverage, and a hypothetical scenario that excluded the mass vaccination campaigns, the researchers estimate that these campaigns have reduced the burden of disease by 27% across Africa and by up to 82% in the countries targeted by the campaigns (an overall reduction of 57% in the 12 targeted countries).
What Do These Findings Mean?
These findings provide a contemporary estimate of the burden of yellow fever in Africa. This estimate is broadly similar to the historic estimate of 200,000 cases and 30,000 deaths annually, which was based on serological survey data obtained from children in Nigeria between 1945 and 1971. Notably, both disease burden estimates are several hundred-fold higher than the average number of yellow fever cases reported annually to WHO, which reflects the difficulties associated with the diagnosis of yellow fever. Importantly, these findings also provide an estimate of the impact of recent mass vaccination campaigns. All these findings have a high level of uncertainty, however, because of the lack of data from both surveillance and serological surveys. Other assumptions incorporated in the researchers' model may also affect the accuracy of these findings. Nevertheless, the framework for burden estimation developed here provides essential new information about the yellow fever burden and the impact of vaccination campaigns and should help the partners of the Yellow Fever Initiative estimate the potential impact of future vaccination campaigns and ensure the efficient allocation of resources for yellow fever control.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides detailed information about yellow fever (in several languages), including photo stories about vaccination campaigns in the Sudan and Mali; it also provides information about the Yellow Fever Initiative (in English and French)
The GAVI Alliance website includes detailed of its support for yellow fever vaccination
The US Centers for Disease Control and Prevention provides information about yellow fever for the public, travelers, and health care providers
The UK National Health Service Choices website also has information about yellow fever
Wikipedia has a page on yellow fever that includes information about the history of the disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4011853  PMID: 24800812
18.  Molecular Evolution of Zika Virus during Its Emergence in the 20th Century 
Zika virus (ZIKV) is a mosquito-borne flavivirus first isolated in Uganda in 1947. Although entomological and virologic surveillance have reported ZIKV enzootic activity in diverse countries of Africa and Asia, few human cases were reported until 2007, when a Zika fever epidemic took place in Micronesia. In the context of West Africa, the WHO Collaborating Centre for Arboviruses and Hemorrhagic Fever at Institut Pasteur of Dakar ( reports the periodic circulation of ZIKV since 1968. Despite several reports on ZIKV, the genetic relationships among viral strains from West Africa remain poorly understood. To evaluate the viral spread and its molecular epidemiology, we investigated 37 ZIKV isolates collected from 1968 to 2002 in six localities in Senegal and Côte d'Ivoire. In addition, we included strains from six other countries. Our results suggested that these two countries in West Africa experienced at least two independent introductions of ZIKV during the 20th century, and that apparently these viral lineages were not restricted by mosquito vector species. Moreover, we present evidence that ZIKV has possibly undergone recombination in nature and that a loss of the N154 glycosylation site in the envelope protein was a possible adaptive response to the Aedes dalzieli vector.
Author Summary
Zika fever is a mosquito-borne illness caused by a flavivirus. Human infections with Zika virus (ZIKV) could cause fever, malaise and cutaneous rash. Despite several ZIKV reports since 1947 when it was first isolated at Zika forest in Uganda, molecular evolution of ZIKV as an emerging agent remains poorly understood. Moreover, despite several ZIKV reports from Africa and Asia, few human cases were notified until 2007 when an epidemic took place in Micronesia. In West Africa, surveillance programs have reported periodic circulation of the virus since 1968. To help fill the gap in understanding ZIKV evolution, 43 ZIKV samples were analyzed. We focused on: (i) adaptive genetic changes including protein glycosylation patterns, (ii) phylogenetic relationship among isolates and their spatiotemporal patterns of spread across Africa and Asia and, (iii) dispersion among vertebrate reservoirs and invertebrate vector species. Our results indicated that ZIKV may have experienced recombination in nature and that, after it emerged from Uganda in the early of the 20th century, it moved to West Africa and Asia in the first half of the century, without any clear preference for host and vector species.
PMCID: PMC3888466  PMID: 24421913
19.  Long-Term Serological Follow-Up of Acute Q-Fever Patients after a Large Epidemic 
PLoS ONE  2015;10(7):e0131848.
Serological follow-up of acute Q-fever patients is important for detection of chronic infection but there is no consensus on its frequency and duration. The 2007–2009 Q-fever epidemic in the Netherlands allowed for long-term follow-up of a large cohort of acute Q-fever patients. The aim of this study was to validate the current follow-up strategy targeted to identify patients with chronic Q-fever.
A cohort of adult acute Q-fever patients, diagnosed between 2007 and 2009, for whom a twelve-month follow-up sample was available, was invited to complete a questionnaire and provide a blood sample, four years after the acute episode. Antibody profiles, determined by immunofluorescence assay in serum, were investigated with a special focus on high titres of IgG antibodies against phase I of Coxiella burnetii, as these are considered indicative for possible chronic Q-fever.
Of the invited 1,907 patients fulfilling inclusion criteria, 1,289 (67.6%) were included in the analysis. At any time during the four-year follow-up period, 58 (4.5%) patients were classified as possible, probable, or proven chronic Q-fever according to the Dutch Q-fever Consensus Group criteria (which uses IgG phase I ≥1:1,024 to as serologic criterion for chronic Q-fever). Fifty-two (89.7%) of these were identified within the first year after the acute episode. Of the six patients that were detected for the first time at four-year follow-up, five had an IgG phase I titre of 1:512 at twelve months.
A twelve-month follow-up check after acute Q-fever is recommended as it adequately detects chronic Q-fever in patients without known risk factors. Additional serological and clinical follow-up is recommended for patients with IgG phase I ≥1:512, as they showed the highest risk to progress to chronic Q-fever.
PMCID: PMC4498618  PMID: 26161658
20.  Spatiotemporal Pattern Analysis of Scarlet Fever Incidence in Beijing, China, 2005–2014 
Objective: To probe the spatiotemporal patterns of the incidence of scarlet fever in Beijing, China, from 2005 to 2014. Methods: A spatiotemporal analysis was conducted at the district/county level in the Beijing region based on the reported cases of scarlet fever during the study period. Moran’s autocorrelation coefficient was used to examine the spatial autocorrelation of scarlet fever, whereas the Getis-Ord Gi* statistic was used to determine the hotspot incidence of scarlet fever. Likewise, the space-time scan statistic was used to detect the space-time clusters, including the relative risk of scarlet fever incidence across all settings. Results: A total of 26,860 scarlet fever cases were reported in Beijing during the study period (2005–2014). The average annual incidence of scarlet fever was 14.25 per 100,000 population (range, 6.76 to 32.03 per 100,000). The incidence among males was higher than that among females, and more than two-thirds of scarlet fever cases (83.8%) were among children 3–8 years old. The seasonal incidence peaks occurred from March to July. A higher relative risk area was mainly in the city and urban districts of Beijing. The most likely space-time clusters and secondary clusters were detected to be diversely distributed in every study year. Conclusions: The spatiotemporal patterns of scarlet fever were relatively unsteady in Beijing from 2005 to 2014. The at-risk population was mainly scattered in urban settings and dense districts with high population, indicating a positive relationship between population density and increased risk of scarlet fever exposure. Children under 15 years of age were the most susceptible to scarlet fever.
PMCID: PMC4730522  PMID: 26784213
scarlet fever; spatiotemporal patterns; children; Beijing
21.  Atmospheric Moisture Variability and Transmission of Hemorrhagic Fever with Renal Syndrome in Changsha City, Mainland China, 1991–2010 
The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by environmental determinants. This study aimed to explore the association between atmospheric moisture variability and the transmission of hemorrhagic fever with renal syndrome (HFRS) for the period of 1991–2010 in Changsha, China.
Methods and Findings
Wavelet analyses were performed by using monthly reported time series data of HFRS cases to detect and quantify the periodicity of HFRS. A generalized linear model with a Poisson distribution and a log link model were used to quantify the relationship between climate and HFRS cases, highlighting the importance of moisture conditions. There was a continuous annual oscillation mode and multi-annual cycle around 3–4 years from 1994 to 1999. There was a significant association of HFRS incidence with moisture conditions and the Multivariate El Niño–Southern Oscillation Index (MEI). Particularly, atmospheric moisture has a significant effect on the propagation of HFRS; annual incidence of HFRS was positively correlated with annual precipitation and annual mean absolute humidity.
The final model had good accuracy in forecasting the occurrence of HFRS and moisture condition can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS), a rodentborne disease caused by Hantaviruses, is characterized by fever, haemorrhage, headache, back pain, abdominal pain, and acute kidney injury. At present, it is endemic in all 31 provinces, autonomous regions, and metropolitan areas in mainland China where human cases account for 90% of the total global cases. Infection rates and population dynamics of hosts are thought to be influenced by climatic factors, especially humidity. Some studies have found that hantaviruses are limited in their spread to high-humidity environments for extended ex vivo stability. Here we provide the evidence that HFRS incidence was strongly associated with moisture conditions, including seasonal variation and annual situation, in Changsha, mainland China, 1991–2010. The results most likely indicate that moisture not only influences growth of food sources that determine rodent population size, thereby affecting the HFRS transmission, but also directly influences rodent activity and hantavirus infectivity. These findings offer insights in understanding possible causes of HFRS transmission, and can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease.
PMCID: PMC3674989  PMID: 23755316
22.  Familial Mediterranean fever in which Crohn’s disease was suspected: a case report 
BMC Research Notes  2014;7:678.
Familial Mediterranean fever is a hereditary autoinflammatory disease, mainly characterized by periodic fever and serositis. The level of awareness about familial Mediterranean fever is far from sufficient, and it is assumed that there may be many patients with this disease who are under observation without an accurate diagnosis.
Case presentation
A 30-year-old Japanese man presented to us with a few years’ history of recurrent episodes of fever, abdominal pain and diarrhea. He often visited a hospital when the attacks occurred; however, acute enteritis was diagnosed each time, and the symptoms resolved spontaneously within a few days. When he noticed a shortening of the interval between the attacks, he visited the hospital again. Upper endoscopy and colonoscopy performed at this hospital revealed no significant abnormal findings. He was then referred to our hospital under the suspicion of a small intestinal disease. Abdominal computed tomography revealed wall thickening and increased density of the mesenteric adipose tissue in the jejunum, which led us to suspect Crohn’s disease. Oral double-balloon enteroscopy was performed; because this revealed only mild mucosal edema in the jejunum, Crohn’s disease was considered to be highly improbable. Based on the patient’s clinical course, we suspected familial Mediterranean fever. As the Livneh criteria for familial Mediterranean fever were satisfied, the patient was started on oral colchicine for the purpose of diagnostic treatment. A definitive diagnosis of familial Mediterranean fever was then made based on the detection of a mutation of the Mediterranean fever gene. A marked reduction in the frequency of attacks was observed in response to colchicine treatment.
Although Crohn’s disease may be considered first in the differential diagnosis of young patients presenting with periodic fever, abdominal pain and diarrhea, the possibility of familial Mediterranean fever should also be borne in mind.
PMCID: PMC4182779  PMID: 25261084
Familial Mediterranean fever; Autoinflammatory disease; Colchicine; Crohn’s disease
23.  Urinary tract infections and post-operative fever in percutaneous nephrolithotomy 
World Journal of Urology  2012;31(5):1135-1140.
To review the incidence of UTIs, post-operative fever, and risk factors for post-operative fever in PCNL patients.
Materials and methods
Between 2007 and 2009, consecutive PCNL patients were enrolled from 96 centers participating in the PCNL Global Study. Only data from patients with pre-operative urine samples and who received antibiotic prophylaxis were included. Pre-operative bladder urine culture and post-operative fever (>38.5°C) were assessed. Relationship between various patient and operative factors and occurrence of post-operative fever was assessed using logistic regression analyses.
Eight hundred and sixty-five (16.2%) patients had a positive urine culture; Escherichia coli was the most common micro-organism found in urine of the 350 patients (6.5%). Of the patients with negative pre-operative urine cultures, 8.8% developed a fever post-PCNL, in contrast to 18.2% of patients with positive urine cultures. Fever developed more often among the patients whose urine cultures consisted of Gram-negative micro-organisms (19.4–23.8%) versus those with Gram-positive micro-organisms (9.7–14.5%). Multivariate analysis indicated that a positive urine culture (odds ratio [OR] = 2.12, CI [1.69–2.65]), staghorn calculus (OR = 1.59, CI [1.28–1.96]), pre-operative nephrostomy (OR = 1.61, CI [1.19–2.17]), lower patient age (OR for each year of 0.99, CI [0.99–1.00]), and diabetes (OR = 1.38, CI [1.05–1.81]) all increased the risk of post-operative fever. Limitations include the use of fever as a predictor of systemic infection.
Approximately 10% of PCNL-treated patients developed fever in the post-operative period despite receiving antibiotic prophylaxis. Risk of post-operative fever increased in the presence of a positive urine bacterial culture, diabetes, staghorn calculi, and a pre-operative nephrostomy.
PMCID: PMC3785702  PMID: 22367718
Urinary tract infection; Percutaneous nephrolithotomy; Kidney stones; PCNL
24.  The Impact of the Demographic Transition on Dengue in Thailand: Insights from a Statistical Analysis and Mathematical Modeling 
PLoS Medicine  2009;6(9):e1000139.
Analyzing data from Thailand's 72 provinces, Derek Cummings and colleagues find that decreases in birth and death rates can explain the shift in age distribution of dengue hemorrhagic fever.
An increase in the average age of dengue hemorrhagic fever (DHF) cases has been reported in Thailand. The cause of this increase is not known. Possible explanations include a reduction in transmission due to declining mosquito populations, declining contact between human and mosquito, and changes in reporting. We propose that a demographic shift toward lower birth and death rates has reduced dengue transmission and lengthened the interval between large epidemics.
Methods and Findings
Using data from each of the 72 provinces of Thailand, we looked for associations between force of infection (a measure of hazard, defined as the rate per capita at which susceptible individuals become infected) and demographic and climactic variables. We estimated the force of infection from the age distribution of cases from 1985 to 2005. We find that the force of infection has declined by 2% each year since a peak in the late 1970s and early 1980s. Contrary to recent findings suggesting that the incidence of DHF has increased in Thailand, we find a small but statistically significant decline in DHF incidence since 1985 in a majority of provinces. The strongest predictor of the change in force of infection and the mean force of infection is the median age of the population. Using mathematical simulations of dengue transmission we show that a reduced birth rate and a shift in the population's age structure can explain the shift in the age distribution of cases, reduction of the force of infection, and increase in the periodicity of multiannual oscillations of DHF incidence in the absence of other changes.
Lower birth and death rates decrease the flow of susceptible individuals into the population and increase the longevity of immune individuals. The increase in the proportion of the population that is immune increases the likelihood that an infectious mosquito will feed on an immune individual, reducing the force of infection. Though the force of infection has decreased by half, we find that the critical vaccination fraction has not changed significantly, declining from an average of 85% to 80%. Clinical guidelines should consider the impact of continued increases in the age of dengue cases in Thailand. Countries in the region lagging behind Thailand in the demographic transition may experience the same increase as their population ages. The impact of demographic changes on the force of infection has been hypothesized for other diseases, but, to our knowledge, this is the first observation of this phenomenon.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, dengue infects 50–100 million people living in tropical and subtropical areas. The four closely related viruses that cause dengue are transmitted to people through the bites of female Aedes aegypti mosquitoes, which acquire dengue virus by feeding on the blood of an infected person. Although some people who become infected with dengue virus have no symptoms, many develop dengue fever, a severe, flu-like illness that lasts for a few days. Other people—more than half a million a year—develop dengue hemorrhagic fever, which causes bleeding from the gums and nose and bruising, or dengue shock syndrome in which circulatory failure also occurs. Both these potentially fatal conditions are associated with sequential infections with dengue virus—nonfatal infection with dengue virus of one type provides lifelong immunity against that type but only temporary protection against infection with dengue viruses of other types. There is no vaccine to prevent dengue and no specific treatment for the disease. However, standard medical care—in particular, replacement of lost fluids—can prevent most deaths from dengue.
Why Was This Study Done?
Historically, dengue has mainly affected young children but, recently, its age distribution has shifted towards older age groups in several Southeast Asian countries, including Thailand. In addition, the interval between large increases in incidence (epidemics) of dengue hemorrhagic fever has lengthened. It is important to know why these changes are happening because they could affect how dengue infections are dealt with in these countries. One idea is that an ongoing shift towards lower birth and death rates (the demographic transition; this occurs as countries move from a pre-industrial to an industrial economy) is reducing dengue transmission rates by reducing the “force of infection” (the rate at which susceptible individuals become infected). As birth and death rates decline, immune individuals account for more of the population so mosquitoes are more likely to bite an immune individual, which reduces the force of infection. Similarly, because susceptible individuals enter the population by being born, changing the birth rate alters the interval between epidemics. In this study, the researchers test whether the demographic transition might be responsible for the changing pattern of dengue infection in Thailand.
What Did the Researchers Do and Find?
The researchers retrieved data on dengue infection, demographic data (the population's age structure and birth and death rates), socioeconomic data, and climatic data for Thailand from 1980 to 2005 from various sources. They then fitted the data on dengue cases to several mathematical models to estimate the force of infection for each year. This analysis suggested that the force of infection has declined by 2% every year since the early1980s. Next, the researchers used statistical methods to show that the strongest predictor of this decline is the increase in the median age of the population (a measure of the average age of the population). Finally, using mathematical simulations of dengue transmission, they showed that a reduced birth rate and a shift in the population's age structure are sufficient to explain the recent shift in the age distribution of dengue cases, the reduction of the force of infection, and the increased interval between epidemics of dengue hemorrhagic fever.
What Do These Findings Mean?
The findings of all modeling studies depend on how the mathematical models are built and the accuracy of the data fed into them. Nevertheless, these findings suggest that recent changes in birth and death rates in Thailand are sufficient to produce the observed changes in the age distribution of dengue and periodicity of dengue outbreaks. One implication of these findings is that other countries in Southeast Asia that follow Thailand in the demographic transition may experience similar shifts in the pattern of dengue infections as the age structure of their populations changes. This means that clinical guidelines for the management of dengue infections in Southeast Asia will need to be adjusted to allow for the increasing age of dengue cases. Finally, although the researchers' calculations show the force of infection has fallen substantially over the past two decades, they also show that when a dengue vaccine becomes available, it will still be necessary to vaccinate most of the population to halt dengue transmission.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Cameron Simmons and Jeremy Farrar
The US Centers for Disease Control and Prevention provides detailed information about dengue fever and dengue hemorrhagic fever (in English and Spanish)
The World Health Organization provides information about dengue and dengue hemorrhagic fever around the world (in several languages) and detailed information about dengue in Southeast Asia
Links to additional information about dengue are provided by MedlinePlus (in English and Spanish)
Wikipedia has a page about the demographic transition (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2726436  PMID: 19721696
25.  Tweeting Fever: Are Tweet Extracts a Valid Surrogate Data Source for Dengue Fever? 
To determine whether Twitter data contains information on dengue-like illness and whether the temporal trend of such data correlates with the incidence dengue or dengue-like illness as identified by city and national health authorities.
Dengue fever is a major cause of morbidity and mortality in the Republic of the Philippines (RP) and across the world. Early identification of geographic outbreaks can help target intervention campaigns and mitigate the severity of outbreaks. Electronic disease surveillance can improve early identification but, in most dengue endemic areas data pre-existing digital data are not available for such systems. Data must be collected and digitized specifically for electronic disease surveillance. Twitter, however, is heavily used in these areas; for example, the RP is among the top 20 producers of tweets in the world. If social media could be used as a surrogate data source for electronic disease surveillance, it would provide an inexpensive pre-digitized data source for resource-limited countries. This study investigates whether Twitter extracts can be used effectively as a surrogate data source to monitor changes in the temporal trend of dengue fever in Cebu City and the National Capitol Region surrounding Manila (NCR) in the RP.
We obtained two sources of ground truth incidence for dengue. The first was daily dengue fever incidence for Cebu City and the NCR taken from the Philippines Integrated Disease Surveillance and Response System (PIDSR). The second ground truth source was fever incidence from Cebu City for 2011. The Cebu City Health Office (CCHO) has monitored fever incidence as a surrogate for dengue fever since the 1980s. Tweets from Cebu City, and the NCR were collected prospectively thru Twitter’s public application program interface. The Cebu City fever ground truth data set was smoothed with a seven day moving average to facilitate comparison to the PIDSR and Twitter data. A vocabulary of words and phrases describing fever and dengue fever in the tweets collected were identified and used to mark relevant tweets. A subset of these ‘fever’ tweets that mentioned fever related to a medical situation were identified. The incidence and the temporal pattern of these medically-relevant tweets were compared with the incidence and pattern of fever and dengue fever in the two ground truth data sets. Pearson correlation coefficient was used to compare the correlation among the different data sets. Noted lag periods were adjusted by moving the data in time and re-computing the correlation coefficient.
26,023,103 tweets were collected from the two geographic regions: 10,303,366 from Cebu City and 15,719,767 tweets from the NCR. 8,814 (0.02%) Tweets contained the word fever and 4099 (0.01% of total) mentioned fever in a medically-relevant context, for example. “…I have a fever…” vs. “…football fever….” The medically-relevant tweets were compared with both ground truth data sets. The correlation between the Tweets and each of the incidence data sets is shown below.
Tweets containing medically-relevant fever references were correlated (p<0.0001) with both fever and dengue fever incidence in the ground truth data sets. The signal indicating fever in the medically-related tweets led the incidence data significantly: by 6 days for the Cebu City fever incidence; and by 12 days for the PIDSR dengue fever incidence. Temporal adjustment to account for observed lag periods increased the correlation coefficient by about one-third in both cases. This was a limited pilot study, but it suggests that Twitter extracts may provide a valid and timely surrogate data source to monitor dengue fever in this population. Further study of the correlation of Twitter and dengue in other areas, and of Twitter with other illnesses is warranted.
PMCID: PMC3692911
Dengue; Social Media; Twitter

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