Dose-response model of Rocky Mountain spotted fever (RMSF) for human.

Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae, which is found in North, Central, and South America. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through tick bites; however, some cases of aerosol transmission also have been reported. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment, it can be fatal. This article develops dose-response models of different routes of exposure for RMSF in primates and humans. The beta-Poisson model provided the best fit to the dose-response data of aerosol-exposed rhesus monkeys, and intradermally inoculated humans (morbidity as end point of response). The average 50% infectious dose among (ID50) exposed human population, N50, is 23 organisms with 95% confidence limits of 1 to 89 organisms. Similarly, ID10 and ID20 are 2.2 and 5.0, respectively. Moreover, the data of aerosol-exposed rhesus monkeys and intradermally inoculated humans could be pooled. This indicates that the dose-response models fitted to different data sets are not significantly different and can be described by the same relationship.

[Rocky Mountain spotted fever in Brazil]. / A febre maculosa no Brasil.

Although the number of confirmed cases of spotted fever has been declining in Brazil since 2005, the mortality rate (20% to 30%) is still high in comparison to other countries. This high mortality rate is closely related to the difficulty in making the diagnosis and starting the correct treatment. Only two groups of antibiotics have proven clinical effectiveness against spotted fever: chloramphenicol and tetracyclines. Until recently, the use of tetracyclines was restricted to adults because of the associated bone and tooth changes in children. Recently, however, the American Academy of Pediatrics and various researchers have recommended the use of doxycycline in children. In more severe cases, chloramphenicol injections are often preferred in Brazil because of the lack of experience with injectable tetracycline. Since early diagnosis and the adequate drug treatment are key to a good prognosis, health care professionals must be better prepared to recognize and treat spotted fever.

Genomic comparison of virulent Rickettsia rickettsii Sheila Smith and avirulent Rickettsia rickettsii Iowa.

Rickettsia rickettsii is an obligate intracellular pathogen that is the causative agent of Rocky Mountain spotted fever. To identify genes involved in the virulence of R. rickettsii, the genome of an avirulent strain, R. rickettsii Iowa, was sequenced and compared to the genome of the virulent strain R. rickettsii Sheila Smith. R. rickettsii Iowa is avirulent in a guinea pig model of infection and displays altered plaque morphology with decreased lysis of infected host cells. Comparison of the two genomes revealed that R. rickettsii Iowa and R. rickettsii Sheila Smith share a high degree of sequence identity. A whole-genome alignment comparing R. rickettsii Iowa to R. rickettsii Sheila Smith revealed a total of 143 deletions for the two strains. A subsequent single-nucleotide polymorphism (SNP) analysis comparing Iowa to Sheila Smith revealed 492 SNPs for the two genomes. One of the deletions in R. rickettsii Iowa truncates rompA, encoding a major surface antigen (rickettsial outer membrane protein A [rOmpA]) and member of the autotransporter family, 660 bp from the start of translation. Immunoblotting and immunofluorescence confirmed the absence of rOmpA from R. rickettsii Iowa. In addition, R. rickettsii Iowa is defective in the processing of rOmpB, an autotransporter and also a major surface antigen of spotted fever group rickettsiae. Disruption of rompA and the defect in rOmpB processing are most likely factors that contribute to the avirulence of R. rickettsii Iowa. Genomic differences between the two strains do not significantly alter gene expression as analysis of microarrays revealed only four differences in gene expression between R. rickettsii Iowa and R. rickettsii strain R. Although R. rickettsii Iowa does not cause apparent disease, infection of guinea pigs with this strain confers protection against subsequent challenge with the virulent strain R. rickettsii Sheila Smith.

[Fiebre manchada de montañas rocosas: experiencia en 5 años de vigilancia activa en un hospital pediátrico de segundo nivel en el noreste de México]. / Rocky mountain spotted fever: five years of active surveillance experience in a second level pediatric hospital in northeastern Mexico.

Introducción: La fiebre manchada de las montañas rocosas (FMMR) es causada por Rickettsia rickettsii. En Coahuila, la región de la Comarca Lagunera se considera una zona endémica. No se han reportado casos en la zona sur del estado, específicamente en la ciudad de Saltillo. Métodos: Estudio prospectivo, reporte de casos. Se incluyeron los casos de niños atendidos en el Hospital del Niño Dr. Federico Gómez Santos en la ciudad de Saltillo, Coah., del mes de septiembre de 2012 a septiembre 2017 con diagnóstico confirmado clínicamente y por reacción en cadena de la polimerasa (PCR) de FMMR. Se presentan los antecedentes epidemiológicos, las características clínicas y evolución de los pacientes. Resultados: Se confirmaron 14 pacientes. La relación masculino:femenino fue de 1.8:1, la edad promedio de los pacientes fue de 7.6 años (18 meses a 13 años). El 42.8% de los pacientes refirió el contacto con perros y el 57.1% afirmó tener contacto con garrapatas. En todos los casos hubo fiebre y exantema purpúrico; alrededor del 70% manifestaron mialgias y artralgias; el 28% tuvo sangrado del tubo digestivo, y el 11% alteraciones neurológicas graves. El 64.2% de los casos recibió tratamiento adecuado con doxiciclina. Fallecieron 8 pacientes, con una tasa de letalidad de 57.1%. Conclusiones: La zona sur de Coahuila debe considerarse una zona endémica para FMMR. El retraso en el diagnóstico y tratamiento favorecen una mayor letalidad. Background: Rocky Mountain Spotted Fever (RMSF) is caused by Rickettsia rickettsii. In Coahuila, Comarca Lagunera is considered an endemic zone; no cases have been reported in the southern zone of the state, specifically in the city of ­Saltillo. Methods: Prospective study, cases report. Children evaluated in the Hospital del Niño Dr. Federico Gómez Santos from September 2012 to September 2017, with clinically and laboratory (by polymerase chain reaction, PCR) confirmed diagnosis of FMMR were included. The epidemiological antecedents, clinical characteristics and patient's evolution are presented. Results: 14 patients were confirmed. The male: female ratio was 1.8: 1, the average age of the patients was 7.6 years (18 months to 13 years). 42.8% reported contact with dogs and 57.1% confirmed contact with ticks. In all cases, there was fever and purpuric rash; around 70% manifested myalgias and arthralgias; 28% presented digestive tract bleeding and 11% had severe neurological alterations. 64.2% of the cases received adequate treatment with doxycycline. Eight patients died with a case fatality rate of 57.1%. Conclusions: The southern zone of Coahuila should be considered an endemic area for FMMR. The delay in diagnosis and treatment favor a greater lethality.

Clinical and laboratory features, hospital course, and outcome of Rocky Mountain spotted fever in children.

OBJECTIVES: To describe the clinical characteristics and course of children with laboratory-diagnosed Rocky Mountain spotted fever (RMSF) and to identify clinical findings independently associated with adverse outcomes of death or discharge with neurologic deficits. STUDY DESIGN: Retrospective chart review of 92 patients at six institutions in the southeastern and southcentral United States from 1990 to 2002. Statistical analyses used descriptive statistics and multiple logistic regression. RESULTS: Children with RMSF presented to study institutions after a median of 6 days of symptoms, which most commonly included fever (98%), rash (97%), nausea and/or vomiting (73%), and headache (61%); no other symptom or sign was present in >50% of children. Only 49% reported antecedent tick bites. Platelet counts were <150,000/mm3 in 59% of children, and serum sodium concentrations were <135 mEq/dL in 52%. Although 86% sought medical care before admission, only 4 patients received anti-rickettsial therapy during this time. Three patients died, and 13 survivors had neurologic deficits at discharge. Coma and need for inotropic support and intravenous fluid boluses were independently associated with adverse outcomes. CONCLUSIONS: Children with RMSF generally present with fever and rash. Delays in diagnosis and initiation of appropriate therapy are unacceptably common. Prognosis is guarded in those with hemodynamic instability or neurologic compromise at initiation of therapy.

Rickettsia as obligate and mycetomic bacteria.

Rickettsiae are well known as intracellular pathogens of animals, humans, and plants and facultative and unorganized symbionts of invertebrates. No close relative of mitochondria has yet been associated with nutritional or developmental dependency of its host cell or organism. We have found a mycetomic Rickettsia that is a strict obligatory symbiont of the parthenogenetic booklouse Liposcelis bostrychophila (Psocoptera). These rickettsiae show an evolutionary transition from a solitary to a primary mycetomic bacterium adapted to the development of its host. These intracellular and intranuclear bacteria reside in specialized cells in several tissues. Their distribution changes markedly with the development of their host. The most advanced phenotype is a paired mycetome in the abdomen, described for the first time for Rickettsia and this host order. The mycetomic rickettsiae of two parthenogenetic book lice species are in the spotted fever group and in the basal limoniae group. While mycetomic bacteria are well known for their metabolic or light-emitting functions, these rickettsiae have an essential role in the early development of the oocyte. Removal of the Rickettsia stops egg production and reproduction in the book louse. In two phylogenetically distant psocopteran species, Rickettsia are shown to be associated with four transitional stages from free bacteria, infected cells, through single mycetocytes to organ-forming mycetomes.

Tick-borne infections in children: epidemiology, clinical manifestations, and optimal management strategies.

Ticks can transmit bacterial, protozoal, and viral infections to humans. Specific therapy is available for several of these infections. Doxycycline is the antimicrobial treatment of choice for all patients, regardless of age, with Rocky Mountain spotted fever, human monocytic ehrlichiosis, or human granulocytic ehrlichiosis. Chloramphenicol has been used to treat these infections in children but is demonstrably inferior to doxycycline. In patients with Mediterranean spotted fever, doxycycline, chloramphenicol, and newer macrolides all appear to be effective therapies. Therapy of Lyme disease depends on the age of the child and stage of the disease. For early localized disease, amoxicillin (for those aged <8 years) or doxycycline (for those aged >/=8 years) is effective. Doxycycline, penicillin V (phenoxymethylpenicillin) or penicillin G (benzylpenicillin) preparations, and erythromycin are all effective treatments for tick-borne relapsing fever. Hospitalized patients with tularemia should receive gentamicin or streptomycin. Doxycycline and ciprofloxacin have each been investigated for the treatment of tularemia in outpatients; however, these agents do not yet have established roles in the treatment of this disease in children. Combination therapy with clindamycin and quinine is preferred for children with babesiosis; the combination of azithromycin and atovaquone also appears promising. Ribavirin has been recently shown to markedly improve survival in patients with Crimean-Congo hemorrhagic fever. The role of antiviral therapy in the treatment of other tick-borne viral infections, including other hemorrhagic fevers and tick-borne encephalitis, is not yet defined.

Cardiopulmonary dynamics in a severe case of Rocky Mountain spotted fever.

A 19-year-old man had multisystem organ failure secondary to Rocky Mountain spotted fever. In addition to renal, cerebral, liver, and gastrointestinal tract involvement he manifested noncardiogenic pulmonary edema and, later, myocardial dysfunction. Aggressive surgical, medical, and monitoring procedures led to recovery. Previously suggested myocardial dysfunction was documented for the first time.

Coagulation and complement studies in Rocky Mountain spotted fever.

A patient with laboratory-acquired Rocky Mountain spotted fever (RMSF) and concomitant influenza virus infection was studied from the third day of clinical illness. The course of his illness was marked by petechial rash, thrombocytopenia, and elevation of fibrin split products. No evidence of complement activation was observed. Plasma proteins were elevated in a pattern characteristic of the "acute phase reaction." The patient recovered completely, and vascular collapse or clinically important disseminated intravascular coagulation had developed. In febrile patients who had influenza or a clinically similar noninfluenzal respiratory syndrome, no changes in coagulation, complement, or plasma proteins developed. We conclude that aberrations in the patient's laboratory values reflected RMSF, and that complement played no critical role in his illness.

Ongoing Cerebral Vasculitis During Treatment of Rocky Mountain Spotted Fever.

BACKGROUND: Rocky Mountain spotted fever is a tickborne infection that produces a systemic small-vessel vasculitis; its prognosis is excellent if appropriate treatment is initiated early. Because the advent of effective antirickettsial therapies predates the widespread use of brain magnetic resonance imaging, there are limited data on the effect of untreated Rocky Mountain spotted fever infection on neuroimaging studies. PATIENT DESCRIPTION: We describe a 7-year-old girl with delayed treatment of Rocky Mountain spotted fever who suffered severe neurological impairment. Serial brain magnetic resonance images revealed a progressive "starry sky appearance," which is proposed to result from the same small vessel vasculitis that causes the characteristic skin rash of this infection. CONCLUSION: Neurological injury can continue to occur despite specific antirickettsial therapy in Rocky Mountain spotted fever. This child's clinical features raise questions about the optimal management of this infection, particularly the utility of immune modulating therapies in cases of delayed treatment and neurological involvement.

Consequences of delayed diagnosis of Rocky Mountain spotted fever in children--West Virginia, Michigan, Tennessee, and Oklahoma, May-July 2000.

Patients with Rocky Mountain spotted fever (RMSF), a tickborne infection caused by Rickettsia rickettsii, respond quickly to tetracycline-class antibiotics (e.g., doxycycline) when therapy is started within the first few days of illness; however, untreated RMSF may result in severe illness and death. Persons aged <10 years have the highest age-specific incidence of RMSF. This report summarizes the clinical course and outcome of RMSF in four children from four regions of the United States and underscores the need for clinicians throughout the United States to consider RMSF in children with rash and fever, particularly those with a history of tick bite or who present during April-September when approximately 90% of RMSF cases occur.

Myocardial function in Rocky Mountain spotted fever: echocardiographic assessment.

Nine patients with Rocky Mountain spotted fever underwent M-mode echocardiographic examination. Increased left ventricular dimension was found in 2 patients and decreased left ventricular shortening fraction in 7. Diminished mean velocity of circumferential fiber shortening, increased left ventricular systolic time intervals ratio, and increased mitral valve E point to ventricular septal separation were found in 6 patients. One patient died and at necropsy diffuse myocarditis was present. Repeat echocardiographic examination was available in the remaining 8 patients at follow-up (mean 10 months). Abnormal E mitral point to ventricular septal separation remained in 3 patients and decreased left ventricular shortening fraction in 2; in 1 there was also increased left ventricular end-diastolic dimension. Thus abnormal left ventricular function and chamber enlargement are frequently present in patients with Rocky Mountain spotted fever.

Ultrastructural study of the response of cells infected in vitro with causative agent of spotted fever group rickettsiosis in Japan.

The response of host cells L929 infected with causative agent of spotted fever group (SFG) rickettsiosis in Japan, the Katayama strain, was studied by electron microscopy. The rickettsiae penetrated the cytoplasm and multiplied here and after prolonged incubation progressed into the dilated cisternae of rough endoplasmic reticulum (rER), the perinuclear space, the deep invaginated nuclear membrane, and then the nucleoplasm of the host cells. The intranuclear rickettsiae showed different states: one type was enclosed by the double membrane of the host cell and the other type was free in the nucleoplasm. In addition to these double membrane-bound and membrane-free intranuclear rickettsiae, various membrane structures, including rER-like structures, were also found in the nucleus. The cells infected with the rickettsiae underwent distinctive morphological alterations which occurred mainly within intracellular membranes of the host cells. These findings indicate the possibility that the intracellular membranes are characteristic cytopathological sites in rickettsia-host cell interaction, and that these alterations may be related to a possible route of rickettsial penetration into the nucleus: passage through vesicles formed from invaginations in the nuclear membrane.

Rickettsia rickettsii infection in the pine vole, Microtus pinetorum: kinetics of infection and quantitation of antioxidant enzyme gene expression by RT-PCR.

The pine vole, Microtus pinetorum, was evaluated as a laboratory animal model for infection with Rickettsia rickettsii. Voles demonstrated signs of acute disease, and 45% of infected animals died following intraperitoneal infection with 3 x 10(6) plaque forming units of R. rickettsii. Spleen, liver, kidney, lung, brain, testes and blood were analyzed for rickettsial burden by a quantitative PCR assay. The distribution of rickettsiae in tissues during the course of infection was determined by immunohistochemical staining and pathological changes in tissues were correlated with the clinical severity of infection. Quantitative RT-PCR assays were designed to measure the mRNA levels of the antioxidant enzyme genes for catalase, glutathione peroxidase, glutathione reductase, heme oxygenase, Cu-Zn superoxide dismutase (SOD) and Mn-SOD, and 2 housekeeping genes, actin and glyceraldehyde phosphate dehydrogenase. Tissues from acutely ill animals on days 2 to 6 of infection, convalescent animals, and uninfected control animals were studied. The number of transcripts of each enzyme gene was determined and compared to the degree of rickettsial infection present. These studies demonstrate that the pine vole is a valuable experimental model for studying infection with R. rickettsii. Our results provide the first experimental evidence that R. rickettsii causes alteration(s) of the anti-oxidant system in vivo.

Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina.

Between November 1993 and March 1994, a cluster 6 pediatric patients with acute febrile illnesses associated with rashes was identified in Jujuy Province, Argentina. Immunohistochemical staining of tissues confirmed spotted fever group rickettsial infection in a patient with fatal disease, and testing of serum of a patient convalescing from the illness by using an indirect immunofluorescence assay (IFA) demonstrated antibodies reactive with spotted fever group rickettsiae. A serosurvey was conducted among 16 households in proximity to the index case. Of 105 healthy subjects evaluated by IFA, 19 (18%) demonstrated antibodies reactive with rickettsiae or ehrlichiae: 4 had antibodies reactive with Rickettsia rickettsii, 15 with Ehrlichia chaffeensis, and 1 with R. typhi. Amblyomma cajennense, a known vector of R. rickettsii in South America, was collected from pets and horses in the area. These results are the first to document rickettsial spotted fever and ehrlichial infections in Argentina.

NF-kappaB activation suppresses host cell apoptosis during Rickettsia rickettsii infection via regulatory effects on intracellular localization or levels of apoptogenic and anti-apoptotic proteins.

Rickettsia rickettsii, a gram-negative and obligate intracellular bacterium, is the causative agent of Rocky Mountain spotted fever. In human infections, the primary target of R. rickettsii infection is vascular endothelium. Our laboratory has shown that activation of nuclear transcription factor-kappa B (NF-kappaB) during R. rickettsii infection of cultured human endothelial cells protects against apoptosis by preventing the activation of apical caspases-8 and -9, and the effector caspase-3. To understand upstream signaling mechanisms, we have determined the effect of NF-kappaB blockade on the status of different Bcl-2 (B-cell lymphoma 2) proteins in this study. Quantitative analysis following TUNEL and Hoechst staining confirmed that infection of endothelial cells with R. rickettsii for 6 h in the presence of a specific NF-kappaB inhibitor, MG132, resulted in induction of apoptosis. Infection-induced apoptosis of EC was associated with decreased level of Bid and accumulation of Bad, while cytosolic level of Bax remained relatively unchanged. Further, the cellular levels of apoptosis antagonist Bcl-2 were found to be down-regulated and apoptogenic mitochondrial proteins Smac and cytochrome c were released into cytoplasm. These results implicate an important regulatory role for NF-kappaB in controlling the intracellular levels and/or localization of pro- as well as anti-apoptotic proteins of Bcl-2 family, the intricate balance of which is a critical determinant of downstream signaling mechanisms governing cell fate during intracellular infection.

Israeli rickettsial spotted fever in children. A review of 54 cases.

We observed and recorded clinical and laboratory data from 54 children with fever and a maculo-papular rash admitted to Soroka Medical Center, Beersheva, Israel suffering from serologically confirmed rickettsial spotted fever. The rash generally began on the palms and soles and extended centripetally to the torso. Other clinical findings included myalgia, headache, hepatomegaly, and splenomegaly. None had a "tache noire". A left shift in the white cells, leucopenia, thrombocytopenia, hyponatraemia and impaired liver function tests were common laboratory abnormalities. All recovered following oral doxycycline therapy. Serious sequelae such as myocarditis, encephalitis, and disseminated intravascular coagulation, as reported in Rocky Mountain spotted fever, did not occur.

Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections.

STUDY OBJECTIVES: To determine whether antipyretic therapy prolongs the course of experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. DESIGN: Retrospective observational study. SETTING: University Center for Vaccine Development. SUBJECTS: Fifty-four volunteers with experimentally induced influenza A, 45 with S. sonnei, and 21 with R. rickettsii infections participated. INTERVENTIONS: Subjects from the six influenza A studies were challenged intranasally. If they met certain criteria, they were offered aspirin or acetaminophen for symptomatic relief. Subjects from the three Shigella studies were challenged with the bacteria and then given trimethoprimsulfamethoxazole. Acetaminophen also could be administered. In the one R. rickettsii trial, subjects were inoculated intradermally and treated with tetracycline. Again, acetaminophen was administered for symptomatic relief. MEASUREMENTS AND MAIN RESULTS: Data, excerpted from subjects' study records, were evaluated using Wilcoxon tests, Spearman's correlation coefficients, and multiple regression analysis. Two-tailed hypotheses with a p value of 0.05 were used for all of the analyses. There was a striking correlation between antipyretic therapy and duration of illness in subjects infected with influenza A and S. sonnei, but not R. rickettsii. CONCLUSIONS: Multivariate analysis suggested that antipyretic therapy prolonged illness in subjects infected with influenza A, but its use was the result of prolonged illness in those infected with S. sonnei. The precise nature of these relationships requires a prospective, randomized, placebo-controlled trial.

Left ventricular dysfunction in Rocky Mountain spotted fever.

Rocky Mountain spotted fever is a serious infectious disease that continues to occur with increasing incidence in various areas of the United States. A high case-fatality ratio (11%) persists in spite of availability of adequate chemotherapeutic agents, and the cardiac involvement may play an important role in the final outcome of some cases. To assess the effect of the disease on left ventricular function 13 patients underwent M-mode echocardiographic examination on admission to a children's hospital. Increased left ventricular dimension was found in 3 patients and decreased left ventricular shortening fraction in 9. Diminished mean velocity of circumferential fiber shortening and increased left ventricular systolic time interval ratios were found in 8 patients and increased mitral valve E point to ventricular septal separation in 9. One patient died and biventricular dilatation with diffuse myocarditis was seen at autopsy. Repeat echo examination was available in 11 patients at follow-up (mean 5 months). Abnormal E mitral point to ventricular septal separation remained in 4 patients and decreased left ventricular shortening fraction in 2. The long-term prognosis for this group is unknown. Myocardial involvement is frequently present in Rocky Mountain spotted fever; close monitoring and aggressive therapeutic approach are essential if the high case-fatality ratio is to be reduced.

Rickettsial disease: classical and modern aspects.

Rickettsial diseases have been reassessed in recent years since they represent an important field in today's medicine. New agents have been described: some are non-pathogenic agents and the others are associated with well-defined or peculiar clinical patterns. In addition, different species of rickettsiosis are found in relation to the geographic areas of the world. Some agents may be defined as variants of older diseases whereas most of the newly described forms of rickettsiosis represent distinct entities with unique epidemiologial and clinical features. Probably the main news regards the group of the spotted fevers. An additional new aspect is linked to the medicine of travellers and tourists. However, this aspect may not be significant for the rickettsial diseases in relation to other human illnesses, such as malaria. Therefore, an investigation into the geographical origin of patients has to enter our routine medical work.