Case Report of Sotalol Induced IgA Vasculitis.

BACKGROUND: IgA vasculitis is the most common form of systemic vasculitis in children but can occur in adults. Inciting antigens include infections, drugs, foods, insect bites, and immunizations. Antibiotics and tumor necrosis factor (TNF) alpha inhibitors are the most common class of drugs that cause IgA vasculitis. Although sotalol and rivaroxaban have been documented to cause leukocytoclastic vasculitis, we have never come across any literature attributing IgA vasculitis to either drug. Additionally, Rocky Mountain spotted fever has not been associated with IgA vasculitis despite being described in cutaneous and systemic vasculitis cases. Here, we present a case of IgA vasculitis triggered by sotalol with challenging differentials, including a recent infection with Rocky Mountain spotted fever, malignancy, and rivaroxaban as possible triggers. CASE PRESENTATION: 68 yr old male with a history of lung cancer treated with resection and chemotherapy 5 years ago is currently in remission, and recently was started on sotalol and rivaroxaban for new-onset paroxysmal atrial fibrillation. He presented with diffuse petechial/purpural rash on the lower limbs, multiple joint pain, severe abdominal pain and rectal bleeds, hemoptysis, and renal dysfunction. IgG titers for RMSF were high. Punch biopsy of skin and renal biopsy were consistent with IgA vasculitis. Sotalol and rivaroxaban were stopped. The patient was treated with oral prednisone, and his condition relatively improved. CONCLUSION: Ig A vasculitis is mostly a self-limiting disease, but adults tend to have a severe course. It is important to diagnose early and identify a trigger. Removing the offending agent or treating the underlying infection is an important aspect of management.

Epidemiology and Clinical Features of Rocky Mountain Spotted Fever from Enhanced Surveillance, Sonora, Mexico: 2015-2018.

Rocky Mountain spotted fever (RMSF), caused by Rickettsia rickettsii, is a severe and potentially fatal tick-borne disease. In 2015, Mexico issued a declaration of epidemiologic emergency in response to ongoing outbreaks of RMSF in northern Mexico. Sonora state is one of the most heavily impacted states in Mexico, with historic case fatality rates (CFRs) of 18%. We summarized data from enhanced surveillance to understand demographic, clinical, and treatment factors associated with the high mortality. We conducted a retrospective review of confirmed and probable RMSF cases reported to the General Directorate of Health Promotion and Disease Prevention in Sonora. A case of RMSF is defined as fever (> 38.5°C), plus two symptoms, and epidemiologic criteria. A confirmed case requires laboratory evidence. During 2015-2018, a total of 510 cases of RMSF were reported; 252 (49%) were in persons aged ≤ 18 years. Case fatality rate was 44% (n = 222). Older age and being confirmed by PCR were associated with fatal outcome (P-value < 0.01). The mean time from onset of symptoms to treatment with doxycycline was 7.9 days (SD ± 5.5). Hot spot analysis revealed neither areas of inordinately high nor low incidence, rather clusters of disease in population centers. The CFR for RMSF in Sonora remains high, and a large proportion of cases are seen in persons aged ≤ 18 years. Whereas previously children experienced a disproportionately high CFR, interventions have reversed this trend. Disease clusters in urban nuclei, but location remains a predictor of fatal outcome.

Selective fragmentation of the trans-Golgi apparatus by Rickettsia rickettsii.

Fragmentation of the Golgi apparatus is observed during a number of physiological processes including mitosis and apoptosis, but also occurs in pathological states such as neurodegenerative diseases and some infectious diseases. Here we show that highly virulent strains of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, induce selective fragmentation of the trans-Golgi network (TGN) soon after infection of host cells by secretion of the effector protein Rickettsial Ankyrin Repeat Protein 2 (RARP2). Remarkably, this fragmentation is pronounced for the trans-Golgi network but the cis-Golgi remains largely intact and appropriately localized. Thus R. rickettsii targets specifically the TGN and not the entire Golgi apparatus. Dispersal of the TGN is mediated by the secreted effector protein RARP2, a recently identified type IV secreted effector that is a member of the clan CD cysteine proteases. Site-directed mutagenesis of a predicted cysteine protease active site in RARP2 prevents TGN disruption. General protein transport to the cell surface is severely impacted in cells infected with virulent strains of R. rickettsii. These findings suggest a novel manipulation of cellular organization by an obligate intracellular bacterium to determine interactions with the host cell.

Fatal Rocky Mountain Spotted Fever along the United States-Mexico Border, 2013-2016.

Rocky Mountain spotted fever (RMSF) is an emerging public health concern near the US-Mexico border, where it has resulted in thousands of cases and hundreds of deaths in the past decade. We identified 4 patients who had acquired RMSF in northern Mexico and subsequently died at US healthcare facilities. Two patients sought care in Mexico before being admitted to US-based hospitals. All patients initially had several nonspecific signs and symptoms, including fever, headache, nausea, vomiting, or myalgia, but deteriorated rapidly without receipt of a tetracycline-class antimicrobial drug. Each patient experienced respiratory failure late in illness. Although transborder cases are not common, early recognition and prompt initiation of appropriate treatment are vital for averting severe illness and death. Clinicians on both sides of the US-Mexico border should consider a diagnosis of RMSF for patients with rapidly progressing febrile illness and recent exposure in northern Mexico.

Rocky Mountain Spotted Fever and Pregnancy: Four Cases from Sonora, Mexico.

We present a series of four pregnant women with Rocky Mountain spotted fever (RMSF) that occurred in Sonora, Mexico, during 2015-2016. Confirmatory diagnoses were made by polymerase chain reaction or serological reactivity to antigens of Rickettsia rickettsii by using an indirect immunofluorescence antibody assay. Each patient presented with fever and petechial rash and was treated successfully with doxycycline. Each of the women and one full-term infant delivered at 36 weeks gestation survived the infection. Three of the patients in their first trimester of pregnancy suffered spontaneous abortions. RMSF should be suspected in any pregnant woman presenting with fever, malaise and rash in regions where R. rickettsii is endemic.

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.

Targeted knockout of the Rickettsia rickettsii OmpA surface antigen does not diminish virulence in a mammalian model system.

UNLABELLED: Strains of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever (RMSF), differ dramatically in virulence despite >99% genetic homology. Spotted fever group (SFG) rickettsiae produce two immunodominant outer membrane proteins, rickettsial OmpA (rOmpA) and rOmpB, which are conserved throughout the SFG and thought to be fundamental to pathogenesis. rOmpA is present in all virulent strains of R. rickettsii but is not produced in the only documented avirulent strain, Iowa, due to a premature stop codon. Here we report the creation of an isogenic ompA mutant in the highly virulent strain Sheila Smith by insertion of intronic RNA to create a premature stop codon 312 bp downstream of the 6,747-bp open reading frame initiation site (int312). Targeted insertion was accomplished using an LtrA group II intron retrohoming system. Growth and entry rates of Sheila Smith ompA::int312 in Vero cells remained comparable to those of the wild type. Virulence was assessed in a guinea pig model by challenge with 100 PFU of either ompA::int312 Sheila Smith or the wild type, but no significant difference in either fever peak (40.5°C) or duration (8 days) were shown between the wild type and the knockout. The ability to disrupt genes in a site-specific manner using an LtrA group II intron system provides an important new tool for evaluation of potential virulence determinants in rickettsial disease research. IMPORTANCE: R. rickettsii rOmpA is an immunodominant outer membrane autotransporter conserved in the spotted fever group. Previous studies and genomic comparisons suggest that rOmpA is involved in adhesion and may be critical for virulence. Little information is available for rickettsial virulence factors in an isogenic background, as limited systems for targeted gene disruption are currently available. Here we describe the creation of an rOmpA knockout by insertion of a premature stop codon into the 5' end of the open reading frame using a group II intron system. An isogenic rOmpA knockout mutation in the highly virulent Sheila Smith strain did not cause attenuation in a guinea pig model of infection, and no altered phenotype was observed in cell culture. We conclude that rOmpA is not critical for virulence in a guinea pig model but may play a role in survival or transmission from the tick vector.

Brazilian spotted fever: the importance of dermatological signs for early diagnosis.

Brazilian spotted fever is an acute febrile infectious disease caused by Rickettsia rickettsii, transmitted by tick bite. As this disease is rare and has high mortality rates in Brazil, the clinical aspects and epidemiological data may help the diagnosis. We report a case of Brazilian spotted fever in a 19-year-old patient who presented maculopapular exanthema in the palmar region and upper limbs, lymphadenopathy, fever, chills, headache, conjunctival hyperemia, nausea, vomiting, dyspnea, myalgia, developing neurological signs and abdominal pain. He was treated with doxycycline with clinical improvement. We emphasize the importance of the recognition of this disease by dermatologists as cutaneous manifestations are the key findings to establish early diagnosis and prevent complications.

Brazilian Spotted Fever: the importance of dermatological signs for early diagnosis

Brazilian spotted fever is an acute febrile infectious disease caused by Rickettsia rickettsii, transmitted by tick bite. As this disease is rare and has high mortality rates in Brazil, the clinical aspects and epidemiological data may help the diagnosis. We report a case of Brazilian spotted fever in a 19-year-old patient who presented maculopapular exanthema in the palmar region and upper limbs, lymphadenopathy, fever, chills, headache, conjunctival hyperemia, nausea, vomiting, dyspnea, myalgia, developing neurological signs and abdominal pain. He was treated with doxycycline with clinical improvement. We emphasize the importance of the recognition of this disease by dermatologists as cutaneous manifestations are the key findings to establish early diagnosis and prevent complications.

Rocky mountain spotted fever characterization and comparison to similar illnesses in a highly endemic area-Arizona, 2002-2011.

BACKGROUND: Rocky Mountain spotted fever (RMSF) has emerged as a significant cause of morbidity and mortality since 2002 on tribal lands in Arizona. The explosive nature of this outbreak and the recognition of an unexpected tick vector, Rhipicephalus sanguineus, prompted an investigation to characterize RMSF in this unique setting and compare RMSF cases to similar illnesses. METHODS: We compared medical records of 205 patients with RMSF and 175 with non-RMSF illnesses that prompted RMSF testing during 2002-2011 from 2 Indian reservations in Arizona. RESULTS: RMSF cases in Arizona occurred year-round and peaked later (July-September) than RMSF cases reported from other US regions. Cases were younger (median age, 11 years) and reported fever and rash less frequently, compared to cases from other US regions. Fever was present in 81% of cases but not significantly different from that in patients with non-RMSF illnesses. Classic laboratory abnormalities such as low sodium and platelet counts had small and subtle differences between cases and patients with non-RMSF illnesses. Imaging studies reflected the variability and complexity of the illness but proved unhelpful in clarifying the early diagnosis. CONCLUSIONS: RMSF epidemiology in this region appears different than RMSF elsewhere in the United States. No specific pattern of signs, symptoms, or laboratory findings occurred with enough frequency to consistently differentiate RMSF from other illnesses. Due to the nonspecific and variable nature of RMSF presentations, clinicians in this region should aggressively treat febrile illnesses and sepsis with doxycycline for suspected RMSF.

Risk factors for fatal outcome from rocky mountain spotted Fever in a highly endemic area-Arizona, 2002-2011.

BACKGROUND: Rocky Mountain spotted fever (RMSF) is a disease that now causes significant morbidity and mortality on several American Indian reservations in Arizona. Although the disease is treatable, reported RMSF case fatality rates from this region are high (7%) compared to the rest of the nation (<1%), suggesting a need to identify clinical points for intervention. METHODS: The first 205 cases from this region were reviewed and fatal RMSF cases were compared to nonfatal cases to determine clinical risk factors for fatal outcome. RESULTS: Doxycycline was initiated significantly later in fatal cases (median, day 7) than nonfatal cases (median, day 3), although both groups of case patients presented for care early (median, day 2). Multiple factors increased the risk of doxycycline delay and fatal outcome, such as early symptoms of nausea and diarrhea, history of alcoholism or chronic lung disease, and abnormal laboratory results such as elevated liver aminotransferases. Rash, history of tick bite, thrombocytopenia, and hyponatremia were often absent at initial presentation. CONCLUSIONS: Earlier treatment with doxycycline can decrease morbidity and mortality from RMSF in this region. Recognition of risk factors associated with doxycycline delay and fatal outcome, such as early gastrointestinal symptoms and a history of alcoholism or chronic lung disease, may be useful in guiding early treatment decisions. Healthcare providers should have a low threshold for initiating doxycycline whenever treating febrile or potentially septic patients from tribal lands in Arizona, even if an alternative diagnosis seems more likely and classic findings of RMSF are absent.

Enhanced protection against Rickettsia rickettsii infection in C3H/HeN mice by immunization with a combination of a recombinant adhesin rAdr2 and a protein fragment rOmpB-4 derived from outer membrane protein B.

BACKGROUND: Two surface proteins of Rickettsia rickettsii, outer membrane protein B (OmpB) and adhesion 2 (Adr2), have been recognized as protective antigens. Herein, the immunization with both OmpB and Adr2 was performed in mice so as to explore whether their combination could induce an enhanced immunoprotection against R. rickettsii infection. METHODS: C3H/HeN mice were immunized with recombinant protein rAdr2 or/and rOmp-4, a fragment derived from OmpB, and then mice were challenged with R. rickettsii. After which rickettsial loads in mice were measured by quantitative PCR. The specific antibodies in mouse sera were determined by ELISA and antigen-specific cytokines secretion by mouse T cells were analyzed in vitro. RESULTS: After challenge with R. rickettsii, the mice immunized with rAdr2 or/and rOmpB-4 had significant lower rickettsial load in livers, spleens, or lungs compared to PBS mock-immunized mice. Particularly, the load in lungs of mice immunized with both rAdr2 and rOmpB-4 was significantly lower than that with either of them. High levels of specific antibodies were detected in sera from mice immunized with rAdr2 or/and rOmpB-4, but the ratios of specific IgG2a to IgG1 induced by their combination were significantly higher than that by either rAdr2 or rOmpB-4. Following stimulation with rAdr2 or/and rOmpB-4, the INF-γ secreted by CD4(+) T cells from infected mice was significantly higher than that by cognate cells from uninfected mice. And the TNF-α secreted by CD4(+) or CD8(+) T cells from infected mice was markedly greater than that by cognate cells from uninfected mice after stimulation by their combination but not either of them. CONCLUSION: The combination of rAdr2 and rOmpB-4 conferred an enhanced protection against R. rickettsii infection in mice, which was mainly dependent on a stronger Th1-oriented immunoresponse with greater INF-γ and TNF-α secretion by antigen-specific T cells and specific IgG2a elicited by the combination.

Clinical profile and predictors of fatal Rocky Mountain spotted fever in children from Sonora, Mexico.

BACKGROUND: Rocky Mountain spotted fever (RMSF) is an increasingly important cause of preventable mortality in children in Sonora, Mexico. Although early treatment with tetracycline has shown to prevent fatal outcome, the disease remains a life-threatening condition, particularly for children. This study describes the clinical factors associated with pediatric mortality due to RMSF in Sonora, in order to guide healthcare practices. METHODS: This is a retrospective analysis of 104 children consecutively hospitalized at the major pediatric hospital of Sonora, diagnosed with RMSF between January 2004 and December 2013. Descriptive statistics and multiple logistic regression were used to identify risk factors for fatal outcome. RESULTS: The case fatality ratio in this cohort was 20.2%. Children were hospitalized after a median of 6 days from onset of symptoms including fever (100%), rash involving palms and soles (88.5%) and headache (79.8%); 90.4% of fatal cases had low platelet counts (<50,000/µL) and 33.3% showed serum creatinine concentrations above the normal value. Acute kidney injury increased mortality, odds ratio (OR(adj)) = 4.84, 95% confidence interval (CI): 1.2-16.2, as well as delay in treatment (≥ 5th day from onset) with doxycycline, OR(adj) = 2.62, 95% CI: 1.24-5.52 and hemorrhage, OR(adj) = 6.11, 95% CI: 1.89-19.69. CONCLUSIONS: RMSF is a public health problem in Sonora. Clinically, fatal cases differ from non-fatal cases in renal function and hemorrhagic manifestations, although these findings may occur too late for a timely intervention. First-line providers must be educated to harbor a timely suspicion of RMSF, and should provide empiric treatment with doxycycline when febrile patients first present for care.

Phylogeography of Rickettsia rickettsii genotypes associated with fatal Rocky Mountain spotted fever.

Rocky Mountain spotted fever (RMSF), a tick-borne zoonosis caused by Rickettsia rickettsii, is among the deadliest of all infectious diseases. To identify the distribution of various genotypes of R. rickettsii associated with fatal RMSF, we applied molecular typing methods to samples of DNA extracted from formalin-fixed, paraffin-embedded tissue specimens obtained at autopsy from 103 case-patients from seven countries who died of RMSF. Complete sequences of one or more intergenic regions were amplified from tissues of 30 (29%) case-patients and revealed a distribution of genotypes consisting of four distinct clades, including the Hlp clade, regarded previously as a non-pathogenic strain of R. rickettsii. Distinct phylogeographic patterns were identified when composite case-patient and reference strain data were mapped to the state and country of origin. The phylogeography of R. rickettsii is likely determined by ecological and environmental factors that exist independently of the distribution of a particular tick vector.

Detection of Rickettsia rickettsii, Rickettsia parkeri, and Rickettsia akari in skin biopsy specimens using a multiplex real-time polymerase chain reaction assay.

BACKGROUND: Rickettsia rickettsii, Rickettsia parkeri, and Rickettsia akari are the most common causes of spotted fever group rickettsioses indigenous to the United States. Infected patients characteristically present with a maculopapular rash, often accompanied by an inoculation eschar. Skin biopsy specimens are often obtained from these lesions for diagnostic evaluation. However, a species-specific diagnosis is achieved infrequently from pathologic specimens because immunohistochemical stains do not differentiate among the causative agents of spotted fever group rickettsiae, and existing polymerase chain reaction (PCR) assays generally target large gene segments that may be difficult or impossible to obtain from formalin-fixed tissues. METHODS: This work describes the development and evaluation of a multiplex real-time PCR assay for the detection of these 3 Rickettsia species from formalin-fixed, paraffin-embedded (FFPE) skin biopsy specimens. RESULTS: The multiplex PCR assay was specific at discriminating each species from FFPE controls of unrelated bacterial, viral, protozoan, and fungal pathogens that cause skin lesions, as well as other closely related spotted fever group Rickettsia species. CONCLUSIONS: This multiplex real-time PCR demonstrates greater sensitivity than nested PCR assays in FFPE tissues and provides an effective method to specifically identify cases of Rocky Mountain spotted fever, rickettsialpox, and R. parkeri rickettsiosis by using skin biopsy specimens.

Features of Brazilian spotted fever in two different endemic areas in Brazil.

Brazilian spotted fever (BSF) caused by Rickettsia rickettsii is the most important rickettsiosis and the only reportable tick-borne disease in Brazil. In Brazil, the hard tick Amblyomma cajennense is the most important BSF vector; however, in São Paulo State, A. aureolatum was also recognized as a vector species in remaining Atlantic forest areas near the metropolitan area of São Paulo city. We analyzed clinical and epidemiological features of BSF cases from two distinct areas where A. cajennense (Area 1) and A. aureolatum (Area 2) are the incriminated vectors. The clinical features demonstrate the same severity pattern of BSF in both endemic areas. Differences in seasonality, patient characteristics (median age and gender), and epidemiological risk factors (animals host contact and vegetation characteristics) were observed and possibly could be attributed to the characteristics of each vector and their typical biological cycle (hosts and environment).

Rocky Mountain spotted fever: 'starry sky' appearance with diffusion-weighted imaging in a child.

We present a case of Rocky Mountain spotted fever encephalitis in a child imaged utilizing diffusion-weighted MRI. Although the imaging and clinical manifestations of this entity have been previously described, a review of the literature did not reveal any such cases reported in children utilizing diffusion-weighted imaging. The imaging findings and clinical history are presented as well as a brief review of this disease.

Rocky Mountain spotted fever in Panama: a cluster description.

Rocky Mountain spotted fever (RMSF) is a tick-borne infection caused by Rickettsia rickettsii. We report a cluster of fatal cases of RMSF in 2007 in Panama, involving a pregnant woman and two children from the same family.  The woman presented with a fever followed by respiratory distress, maculopapular rash, and an eschar at the site from which a tick had been removed.  She died four days after disease onset.  This is the second published report of an eschar in a patient confirmed by PCR to be infected with R. rickettsii.  One month later, the children presented within days of one another with fever and rash and died three and four days after disease onset. The diagnosis was confirmed by immunohistochemistry, PCR and sequencing of the genes of R. rickettsii in tissues obtained at autopsy. 

Infecção rickettsial em Cerro Largo, Rio Grande do Sul / Rickettsial infection in Cerro Largo, State of Rio Grande do Sul, Brazil

O presente estudo teve por objetivo avaliar, por imunofluorescência indireta, infecções ricketsiais em animais e humanos assintomáticos da área rural de Cerro Largo, RS. Dezesseis (51.6%) equinos, seis (22.3%) cães e oito (29.6%) humanos mostraram anticorpos reagentes (título <64) para Ricksettia rickettsii e para Ricksettia parkeri. Os estudos sorológicos indicaram que equinos, cães e humanos entraram em contato com rickettsias do grupo da febre maculosa nesse município. Dois cães mostraram títulos de R. parkeri no mínimo quatro vezes maior que os demais agentes ricketsiais testados e sugerindo que R. parkeri ou um genótipo próximo está circulando na região.