Developments in the scientific and clinical understanding of autoinflammatory disorders

The autoinflammatory diseases, also known as periodic fever syndromes, are disorders of innate immunity which can be inherited or acquired and which cause recurrent, self-limiting, seemingly spontaneous episodes of systemic inflammation and fever in the absence of autoantibody production or infection. There has been much recent progress in elucidating their aetiologies and treatment. With the exception of familial Mediterranean fever, which is common in certain populations, autoinflammatory diseases are mostly rare but should not be overlooked in the differential diagnosis of recurrent fevers since DNA diagnosis and effective therapies are available for many of them.     

Fever in the Neutropenic Patient

A total of 100 consecutive episodes of fever of 101° F (38·3°C) or above in 56 neutropenic patients have been investigated. All the patients had either acute leukaemia or aplastic anaemia. A cause for the fever was found in 68 of these episodes, in 87% of which it was due to infection. The commonest single finding was septicaemia (30 episodes). Only two episodes of fever could be ascribed solely to the underlying malignant disease.Infection should be assumed to be present and the cause of fever in neutropenic patients until proved otherwise.     

Body temperature, behavior, and plasma cortisol changes induced by chronic infusion of Staphylococcus aureus in goats

Most experimentally induced fevers are acute, usually lasting approximately 6-12 h, and thus do not mimic chronic natural fevers, which can extend over several days or more. To produce a model of chronic natural fever, we infused eight goats (Capra hircus) intravenously with 2 ml of 2 x 10(11) cell walls of Staphylococcus aureus (S. aureus) for 6 days using osmotic infusion pumps (10 microl/h) while measuring changes in body temperature, behavior, and plasma cortisol concentration. Seven control animals were infused with sterile saline. Abdominal temperature-sensitive data loggers and osmotic infusion pumps were implanted under halothane anesthesia. To compare our new model with existing models of experimental fever, we also administered 2-ml bolus intravenous injections of 2 x 10(11) S. aureus cell walls, 0.1 microg/kg lipopolysaccharide (Escherichia coli, serotype 0111:B4), and sterile saline in random order to six other goats. Bolus injection of lipopolysaccharide and S. aureus induced typical acute phase responses, characterized by fevers lasting approximately 6 h, sickness behavior, and increased plasma cortisol concentration. Infusion of S. aureus evoked prolonged fevers, which lasted for approximately 3 days, starting on day 4 of infusion (ANOVA, P < 0.05), and did not disrupt the normal circadian rhythm of body temperature. However, pyrogen infusion did not cause plasma cortisol concentration to rise (ANOVA, P > 0.05) or the expression of sickness behavior. In conclusion, infusion of S. aureus produced a fever response resembling that of sustained natural fevers but did not elicit the cortisol and behavioral responses that often are described clinically and during short-term experimental fevers.     

Clinical Features and Patient Management of Lujo Hemorrhagic Fever

Background

In 2008 a nosocomial outbreak of five cases of viral hemorrhagic fever due to a novel arenavirus, Lujo virus, occurred in Johannesburg, South Africa. Lujo virus is only the second pathogenic arenavirus, after Lassa virus, to be recognized in Africa and the first in over 40 years. Because of the remote, resource-poor, and often politically unstable regions where Lassa fever and other viral hemorrhagic fevers typically occur, there have been few opportunities to undertake in-depth study of their clinical manifestations, transmission dynamics, pathogenesis, or response to treatment options typically available in industrialized countries.

Methods and Findings

We describe the clinical features of five cases of Lujo hemorrhagic fever and summarize their clinical management, as well as providing additional epidemiologic detail regarding the 2008 outbreak. Illness typically began with the abrupt onset of fever, malaise, headache, and myalgias followed successively by sore throat, chest pain, gastrointestinal symptoms, rash, minor hemorrhage, subconjunctival injection, and neck and facial swelling over the first week of illness. No major hemorrhage was noted. Neurological signs were sometimes seen in the late stages. Shock and multi-organ system failure, often with evidence of disseminated intravascular coagulopathy, ensued in the second week, with death in four of the five cases. Distinctive treatment components of the one surviving patient included rapid commencement of the antiviral drug ribavirin and administration of HMG-CoA reductase inhibitors (statins), N-acetylcysteine, and recombinant factor VIIa.

Conclusions

Lujo virus causes a clinical syndrome remarkably similar to Lassa fever. Considering the high case-fatality and significant logistical impediments to controlled treatment efficacy trials for viral hemorrhagic fever, it is both logical and ethical to explore the use of the various compounds used in the treatment of the surviving case reported here in future outbreaks. Clinical observations should be systematically recorded to facilitate objective evaluation of treatment efficacy. Due to the risk of secondary transmission, viral hemorrhagic fever precautions should be implemented for all cases of Lujo virus infection, with specialized precautions to protect against aerosols when performing enhanced-risk procedures such as endotracheal intubation.     

Site of action of calcium channel blockers in inhibiting endogenous pyrogen fever in rats.

We have demonstrated that the Ca2+ channel blocker verapamil, administered intravenously, exerts an antipyretic effect on the febrile responses of rats to intravenously injected endogenous pyrogen (EP). We have also shown that the same intravenous dose of verapamil is ineffective in blocking fevers induced by the microinjection of exogenous prostaglandin E (PGE) into the organum vasculosum laminae terminalis (OVLT) of rats. Experiments were conducted to determine whether the site of this verapamil antipyresis was in the OVLT itself. The febrile responses of six male Sprague-Dawley rats to EP were determined at thermoneutrality. Verapamil (10 micrograms/rat) was microinjected directly into the OVLT, and the febrile responses to the EP dose were redetermined 15-30 min later. In every case the EP fevers were attenuated after verapamil pretreatment. Intra-OVLT injections of verapamil alone were without effect on body temperature. When the same dose of verapamil was injected into the OVLT 15 min before the injection of PGE into the same site, it had no effect on the ensuing PGE-induced fever. In view of the fact that less than 1/250th of the effective systemic dose of verapamil, when injected into the OVLT, was equally effective in blocking the EP fevers, we conclude that verapamil acts within the OVLT to block fever rather than peripherally. Furthermore, because verapamil administered into the OVLT does not block PGE fevers, it is unlikely that PGE produces fever by acting as a Ca2+ ionophore on hypothalamic neurons.     

Differences in endogenous pyrogen fevers induced by iv and icv routes in rabbits

We have compared the characteristics of fevers produced by endogenous pyrogen administered by the intravenous (iv) and by the intracerebroventricular (icv) routes in conscious rabbits. Fevers induced by the intracerebroventricular route have a longer latency to onset, a less steep rise in body temperature, and a longer time to peak elevation in body temperature than do fevers induced by the intravenous route. Furthermore, a dose of indomethacin (2 mg/kg) administered intravenously, which is effective in markedly attenuating fevers produced by the intravenous route, was completely without effect on fevers induced by the intracerebroventricular route. On the other hand, when indomethacin (500 micrograms) was infused intracerebroventricularly, it markedly reduced fevers induced by the subsequent injection of endogenous pyrogen into the contralateral cerebral ventricle, but such pretreatment had little effect on fevers elicited by intravenous injections of endogenous pyrogen. It is concluded that the sites of action of endogenous pyrogen in response to intravenous injections of pyrogen are different from those responding to intracerebroventricular injections of pyrogen and that this is manifest in several distinct differences in the characteristics of the two fevers. These results indicate that the intracerebroventricular model of fever production is not appropriate for the study of the normal pathogenesis of fever.     

Forty-Day Fever: An Epidemic of Cytomegalovirus Disease in a Renal Transplant Population

An epidemic of cytomegalovirus disease (CMV) occurred in 38 percent of 34 renal transplant recipients during an 18-month period. A characteristic clinical pattern was noted: 40 days following transplantation, daily fevers recurred for periods of four to six weeks. This fever in conjunction with a diffuse interstitial pneumonitis and impaired hepatic and renal function constituted a diagnostic tetrad. Of all the laboratory techniques, throat and urine cultures were the most consistent in confirming the diagnosis.Analysis of the epidemic implicated the communal hemodialysis unit as the source of exposure to the virus. CMV was not seen in the first 86 patients who received transplants in the program, but with increasing use of hemodialysis, the percentage of patients with positive serologic reaction for CMV increased dramatically.     

Effects of nitric oxide synthase inhibitors on the febrile response to muramyl dipeptide and lipopolysaccharide in rats

We have administered aminoguanidine, a relatively specific inhibitor of inducible nitric oxide synthase, and N-nitro-L-arginine methyl ester (L-NAME), an unspecific nitric oxide synthase inhibitor, to rats made febrile with the gram-positive pyrogen, muramyl dipeptide and gram-negative pyrogen, lipopolysaccharide. Sprague-Dawley rats, housed individually at approximately 25 degrees C with a 12:12 h light:dark cycle (lights on 0700 hours), were injected (at 0900 hours) intraperitoneally with 50 mg/kg aminoguanidine, 25 mg/kg or 50 mg/kg L-NAME, and intramuscularly with 500 microg/kg muramyl dipeptide or 100 microg/kg lipopolysaccharide. Pyrogen injections were spaced at least 14 days apart. Body temperature was measured throughout the study in unrestrained animals using radio-telemetry. Neither muramyl dipeptide nor lipopolysaccharide-induced fevers were affected by aminoguanidine. However, L-NAME administration inhibited muramyl dipeptide and lipopolysaccharide-induced fevers, but only for the 1st 2-4 h of the fevers (two-way ANOVA, P<0.05). After the initial inhibition, lipopolysaccharide fevers developed normally. Therefore, constitutively expressed nitric oxide synthase appears to be involved in the initial phases of fever genesis of gram-negative and gram-positive fevers in rats. On the other hand, inducible nitric oxide synthase appears not to play a role in these fevers.     

A role for natriuretic peptide in lipopolysaccharide-induced fever in Pekin ducks (Anas platyrhynchos): is natriuretic peptide an endogenous antipyretic in birds?

The febrile mechanism in all vertebrates involves endogenous molecules which mediate and attenuate the fever response. This mechanism is considered phylogenetically conserved, and the molecules are thought to be analogous in different species. The above notion is supported by evidence which show avian and mammalian fevers to have similar mediators. There is, however, a paucity of information regarding the modulators of the avian febrile response. Natriuretic peptides were shown to modulate mammalian fevers and, although natriuretic peptides are also present in birds, they have never been investigated in the context of fever. We induced fever in Pekin ducks with lipopolysaccharide and, at the same time, treated the animals with natriuretic peptide antiserum at a dose that effectively inhibited the known renal actions of endogenously secreted natriuretic peptide. We compared fever responses after ducks received either the antiserum or an appropriate control along with the lipopolysaccharide. The antiserum did not attenuate the fever responses of ducks. Our results differ from the results of a study in rats, which demonstrated natriuretic peptides to be potently antipyretic. This molecule seems to be antipyretic in mammals but not in ducks. We suggest a species variation regarding the ability of natriuretic peptides to modulate fever.     

Viral haemorrhagic fevers--evolution of the epidemic potential

In this review modern data on dangerous and particularly dangerous viral haemorrhagic fevers caused by a group of viruses belonging to the families of phylo-, arena-, flavi-, bunya- and togaviruses are presented. Morbidity rates and epidemics caused by Marburg virus, Ebola fever virus, Lassa fever virus, Argentinian and Bolivian haemorrhagic fever viruses, dengue haemorrhagic fever virus, Crimean haemorrhagic fever virus, Hantaviruses are analyzed. Mechanisms of the evolution of the epidemic manifestation of these infections are considered. The importance of the development of tools and methods of diagnosis, rapid prevention and treatment of exotic haemorrhagic fevers is emphasized.     

Human–Wildlife Interactions Predict Febrile Illness in Park Landscapes of Western Uganda

Fevers of unknown origin complicate treatment and prevention of infectious diseases and are a global health burden. We examined risk factors of self-reported fever—categorized as “malarial” and “nonmalarial”—in households adjacent to national parks across the Ugandan Albertine Rift, a biodiversity and emerging infectious disease hotspot. Statistical models fitted to these data suggest that perceived nonmalarial fevers of unknown origin were associated with more frequent direct contact with wildlife and with increased distance from parks where wildlife habitat is limited to small forest fragments. Perceived malarial fevers were associated with close proximity to parks but were not associated with direct wildlife contact. Self-reported fevers of any kind were not associated with livestock ownership. These results suggest a hypothesis that nonmalarial fevers in this area are associated with wildlife contact, and further investigation of zoonoses from wildlife is warranted. More generally, our findings of land use–disease relationships aid in hypothesis development for future research in this social-ecological system where emerging infectious diseases specifically, and rural public health provisioning generally, are important issues.     

Population Explosions of Tiger Moth Lead to Lepidopterism Mimicking Infectious Fever Outbreaks

Lepidopterism is a disease caused by the urticating scales and toxic fluids of adult moths, butterflies or its caterpillars. The resulting cutaneous eruptions and systemic problems progress to clinical complications sometimes leading to death. High incidence of fever epidemics were associated with massive outbreaks of tiger moth Asota caricae adult populations during monsoon in Kerala, India. A significant number of monsoon related fever characteristic to lepidopterism was erroneously treated as infectious fevers due to lookalike symptoms. To diagnose tiger moth lepidopterism, we conducted immunoblots for tiger moth specific IgE in fever patients’ sera. We selected a cohort of patients (n = 155) with hallmark symptoms of infectious fevers but were tested negative to infectious fevers. In these cases, the total IgE was elevated and was detected positive (78.6%) for tiger moth specific IgE allergens. Chemical characterization of caterpillar and adult moth fluids was performed by HPLC and GC-MS analysis and structural identification of moth scales was performed by SEM analysis. The body fluids and chitinous scales were found to be highly toxic and inflammatory in nature. To replicate the disease in experimental model, wistar rats were exposed to live tiger moths in a dose dependant manner and observed similar clinico-pathological complications reported during the fever epidemics. Further, to link larval abundance and fever epidemics we conducted cointegration test for the period 2009 to 2012 and physical presence of the tiger moths were found to be cointegrated with fever epidemics. In conclusion, our experiments demonstrate that inhalation of aerosols containing tiger moth fluids, scales and hairs cause systemic reactions that can be fatal to human. All these evidences points to the possible involvement of tiger moth disease as a major cause to the massive and fatal fever epidemics observed in Kerala.     

Ixodoid ticks on rodents in the deserts of South Kazakhstan

The tick fauna of rodents was studied in the Muyunkum (Chu-Talas interfluve) and Eastern Kyzylkum deserts and in the west of Betpakdala. Hyalomma asiaticum asiaticum, Haemaphysalis erinacei turanica, and Ornithodoros tartakovskyi ticks were dominant in all the desert regions but the degree of dominance of individual species varied in different deserts. The greatest number of ticks parasitized Rhombomys opimus and Spermophilus fulvus. The ticks parasitizing rodents are vectors of Crimean-Congo hemorrhagic fever, Q fever, tick-borne spotted fevers, and borrelioses.     

Rural-urban differences in maternal responses to childhood fever in South East Nigeria

Background

Childhood fevers due to malaria remain a major cause of morbidity and mortality among under-five children in Nigeria. The degree of vulnerability perceived by mothers will affect their perception of the severity and threat of their child''s fever and the patterns of health care use. This study was undertaken to compare maternal responses to childhood fever in urban and rural areas of Enugu, south east Nigeria.

Methodology/Principal Findings

Data was collected with pre-tested interviewer-administered questionnaires from 276 and 124 urban and rural households respectively. In each household, only one woman aged 15–49 years who had lived in each of the urban and rural communities for at least one year and had at least one child less than 5 years old was interviewed. Malaria was mentioned as the commonest cause of childhood fevers. Rural mothers were more likely to recognize danger signs and symptoms than urban mothers. Rural mothers use more of informal than formal health services, and there is more home management of the fever with urban than rural mothers. Chloroquine, ACT, SP and Paracetamol are the main drugs given at home for childhood fevers, but the rural mothers were more likely to use leftover drugs from previous treatment to treat the fevers than urban mothers. The urban respondents were also more likely to use a preventive measure. Urban mothers sought actions faster than rural mothers and the total cost of treatment was also higher in urban areas.

Conclusions/Significance

Both urban and rural mothers are aware that malaria is the major cause of childhood fevers. Although rural mothers recognize childhood fever and danger signs better than urban mothers, the urban mothers'' responses to fever seem to be better than that for rural mothers. These responses and differences may be important for geographical targeting by policy makers for malaria interventions.     

Socioeconomic status and the prevalence of fever in children under age five: evidence from four sub-Saharan African countries

ABSTRACT: BACKGROUND: The burden of fevers remains enormous in sub-Saharan Africa. While several efforts at reducing the burden of fever have been made at the macro level, the relationship between socioeconomic status and fever prevalence has been inconclusive at the household and individual levels. The purpose of this study was to examine how individual and household socioeconomic status influences the prevalence of fever among children under age five in four sub-Saharan African countries. METHODS: The study used data from the 2008 Demographic and Health Survey (DHS) from Ghana, Nigeria, Kenya and Sierra Leone with a total of 38,990 children below age five. A multi-level random effects logistic model was fitted to examine the socioeconomic factors that influence the prevalence of fever in the two weeks preceding the survey. Data from the four countries were also combined to estimate this relationship, after country-specific analysis. RESULTS: The results show that children from wealthier households reported lower prevalence of fever in Ghana, Nigeria and Kenya. Result from the combined dataset shows that children from wealthier households were less likely to report fever. In general, vaccination against fever-related diseases and the use of improved toilet facility reduces fever prevalence. The use of bed nets by children and mothers did not show consistent relationship across the countries. CONCLUSION: Poverty does not only influence prevalence of fever at the macro level as shown in other studies but also the individual and household levels. Policies directed towards preventing childhood fevers should take a close account of issues of poverty alleviation. There is also the need to ensure that prevention and treatment mechanisms directed towards fever related diseases (such as malaria, pneumonia, measles, diarrhoea, polio, tuberculosis etc) are accessible and effectively used.     

Comparison of febrile responsiveness of rats and rabbits to endogenous pyrogen

The fever responses of rats and rabbits were compared in detail using a single common source of semipurified endogenous pyrogen prepared from human monocytes. The characteristics and dynamics of the fever-response curves for each species were examined and their dose-response curves were determined and compared. The fevers displayed by rats were qualitatively similar to those of rabbits, but, typically, they developed and terminated more rapidly than those of rabbits. Rabbits were much more sensitive to the endogenous pyrogen than rats. The threshold dose of pyrogen required to elicit a fever was 5 times lower in the rabbit, and the slope of the rabbit's dose-response curve was 1.5 times steeper than that of the rat. The maximum fevers attainable in rabbits were approximately twice those attainable in rats. It was also shown that the more rapid febrile responses of the rat were not due to the 10-fold smaller mass of the rat; instead, we proposed that this difference was more likely due to a closer diffusional proximity of the pyrogen receptor sites to the circulation in rats. The lower sensitivity of the rat to endogenous pyrogen was attributed to a relative insensitivity of the pyrogen receptor sites in rats in the translation of the endogenous pyrogen stimulus into fever.     

Galen's intermittent fever

In his comprehensive Oeuvre, Galen of Pergamon, who interpreted and perfected Hippocratic medicine, made many times and in various contexts mention of the intermittent fevers, among which malaria undoubtedly held a prominent position. The following article gives an outline of Galen's theoretical concept of this infectious disease, which was of utmost importance for the history of Italy. Galen describes three different types of intermittent fevers, of which, according to his theory of humoural pathology, each one is caused by a special humour with its respective qualities. Thus the quotidian fever is caused by phlegm, the tertian fever by the yellow bile and the quartan fever by the black bile. Apart from the three basic types of fever Galen describes a number of other mixed forms which can either be developed out of identical types or out of different ones. A mixture of a special kind is febris semitertiana: a continuous quotidian is accompanied by an intermittent tertian. It is the worst and most dangerous of these fevers. On the whole Galen's theory of malaria is a paradigm for his forming the reality of diseases on the basis of his pre-knowledge of humoural pathology into a closed system of theory.     

Estimating the Number of Paediatric Fevers Associated with Malaria Infection Presenting to Africa's Public Health Sector in 2007

Background

As international efforts to increase the coverage of artemisinin-based combination therapy in public health sectors gather pace, concerns have been raised regarding their continued indiscriminate presumptive use for treating all childhood fevers. The availability of rapid-diagnostic tests to support practical and reliable parasitological diagnosis provides an opportunity to improve the rational treatment of febrile children across Africa. However, the cost effectiveness of diagnosis-based treatment polices will depend on the presumed numbers of fevers harbouring infection. Here we compute the number of fevers likely to present to public health facilities in Africa and the estimated number of these fevers likely to be infected with Plasmodium falciparum malaria parasites.

Methods and Findings

We assembled first administrative-unit level data on paediatric fever prevalence, treatment-seeking rates, and child populations. These data were combined in a geographical information system model that also incorporated an adjustment procedure for urban versus rural areas to produce spatially distributed estimates of fever burden amongst African children and the subset likely to present to public sector clinics. A second data assembly was used to estimate plausible ranges for the proportion of paediatric fevers seen at clinics positive for P. falciparum in different endemicity settings. We estimated that, of the 656 million fevers in African 0–4 y olds in 2007, 182 million (28%) were likely to have sought treatment in a public sector clinic of which 78 million (43%) were likely to have been infected with P. falciparum (range 60–103 million).

Conclusions

Spatial estimates of childhood fevers and care-seeking rates can be combined with a relational risk model of infection prevalence in the community to estimate the degree of parasitemia in those fevers reaching public health facilities. This quantification provides an important baseline comparison of malarial and nonmalarial fevers in different endemicity settings that can contribute to ongoing scientific and policy debates about optimum clinical and financial strategies for the introduction of new diagnostics. These models are made publicly available with the publication of this paper. Please see later in the article for the Editors'' Summary     

Invited review: cytokine regulation of fever: studies using gene knockout mice.

Fever is defined as a regulated rise in body temperature. The regulation of this phenomenon is accomplished by the actions of two types of endogenous cytokines, some functioning as pyrogens and others as antipyretics. Previous data obtained with the use of traditional pharmacological techniques, such as the injection of neutralizing antibodies, implicate interleukin (IL)-1 and IL-6 as endogenous pyrogens or inducers of fever. In almost all instances in which the endogenous actions of IL-1 or IL-6 are antagonized, fevers are attenuated. Other cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and IL-10, are thought to act as endogenous antipyretics or inhibitors of fever. In several studies, the inhibition of TNF action has enhanced fever. Recently, mice genetically engineered to lack cytokines or their receptors in all tissues of the body have been used to examine the regulation of IL-1, IL-6, TNF, and IL-10 on fever. Data obtained with these mice shed new light on our understanding of cytokine interactions in fever and, in some instances, contradict data obtained with pharmacological methods. This review summarizes the responses of cytokine and cytokine receptor knockout mice to fevers induced by lipopolysaccharide, turpentine, and sepsis.