Rickettsiosis Subcommittee Report to the Tick-Borne Disease Working Group

Disclaimer

Information and opinions in this report do not necessarily reflect the opinions of the Working Group, the U.S. Department of Health and Human Services, or any other component of the Federal Government. Readers should not consider the report or any part of it to be guidance or instruction regarding the diagnosis, care, or treatment of tick-borne diseases or to supersede in any way existing guidance. All subcommittee members actively participated in the development of this report. Members voted to approve submission of the report to the Working Group and on the wording of each of the possible actions contained in the report. The vote to submit the report indicates general agreement with the content of the document, but it does not necessarily indicate complete agreement with each and every statement in the full report.

Background

Rickettsia pathogens and associated rickettsial diseases were not a primary focus area of the first Tick-Borne Disease Working Group report; nonetheless, as a group they pose a significant impact on U.S. public health. Based on passive surveillance, more than 5,500 cases of tick-borne spotted fever group (SFG) rickettsioses (caused by Rickettsiae in the spotted fever group) were reported in 2018 ("CDC Nationally Notifiable Infectious Diseases and Conditions, United States: Annual Tables," 2018). These cases do not reflect the true incidence of infections, since many cases go unreported. Unfortunately, 99% of reported cases are not confirmed. At present, serologic diagnosis does not distinguish between patients exposed to the various SFG Rickettsia species that human-biting ticks carry in the U.S. Patients exposed to non-pathogenic rickettsiae develop antibodies that cannot be distinguished from those stimulated by pathogenic species, including the highly virulent Rickettsia rickettsii, the cause of Rocky Mountain spotted fever, which results in fatality rates approaching 23% without appropriate treatment. Exposure rates are relatively high, with 10-20% of healthy persons residing in the region of the U.S. where lone star ticks predominate demonstrating anti-SFG rickettsial antibodies (Marshall et al., 2003). Several hurdles exist that prevent accurate diagnosis and treatment: 1) there is no generally available test for diagnosis of acute infection; 2) knowledge and awareness of laboratory diagnostics and appropriate treatment by many physicians are lacking; 3) diagnosis based on clinical manifestations early in the course of illness is very difficult; and 4) only a limited number of antibiotics are effective (Marshall et al., 2003). The need for effective recognition, diagnosis and treatment is especially critical given the absence of any approved vaccine to prevent rickettsial infections in humans.

The Rickettsiosis Subcommittee identified three primary goals: 1) to describe the health impact of tick-borne rickettsial diseases in the U.S., 2) to determine obstacles to reduction of morbidity and mortality caused by tick-borne rickettsial diseases in the U.S., and 3) to identify gaps in knowledge and implementation that research may help resolve. The Subcommittee identified several specific issues to be addressed, including identifying the species of rickettsial pathogens prevalent in the U.S., epidemiology, surveillance (clinical and environmental), true incidence of diseases, geographic prevalence of lone star ticks, point-of-care diagnostic tests, treatment of children under 12 with doxycycline, undertreating versus overtreating, and lastly, public and clinical education.

Methods

Subcommittee Membership

The Rickettsiosis Subcommittee was established to leverage member expertise, balance a range of perspectives, and thoroughly examine several aspects of diagnostics, treatment, and prevention of a range of tick-borne rickettsial diseases based on the published scientific literature, current research efforts, and exchanges between subcommittee members. The composition of the Subcommittee and expertise of the subcommittee Co-Chairs and members are outlined in Table 1.

Table 1: Members of the Rickettsiosis Subcommittee

Subcommittee Members	Type	Stakeholder Group	Expertise
Co-Chair David Walker, MD, Professor, Department of Pathology, The Carmage and Martha Walls Distinguished University Chair in Tropical Diseases; Executive Director, University of Texas Medical Branch Center for Biodefense and Emerging Infectious Diseases	Public	Scientist and physician	Tropical and emerging zoonotic vector-borne infectious diseases, 48 years of experience on vector-borne diseases including Rocky Mountain spotted fever and Mediterranean spotted fever with emphasis on clinical manifestations, diagnostics, and epidemiology. 45 years of research experience on pathogenesis, immunity, and diagnosis of spotted fever rickettsioses
CAPT Estella Jones, DVM, Deputy Director, Office of Counterterrorism and Emerging Threats, Office of the Chief Scientist, Office of the Commissioner, U.S. Food and Drug Administration (FDA), U.S. Department of Health and Human Services (HHS)	Federal	Veterinarian and scientist	Health emergencies involving chemical, biological, radiological, nuclear, and emerging infectious diseases; Biosafety Level-4 and zoonotic diseases
CDR Todd Myers, PhD, (Alternate to Estella Jones) Office of Counterterrorism and Emerging Threats, Office of the Chief Scientist, Office of the Commissioner, FDA, HHS	Federal	Scientist	Health emergencies involving chemical, biological, radiological, nuclear, and emerging infectious diseases; Regulatory science and pathogens of high consequence
David N. Gaines, PhD, Public Health Entomologist, Virginia Department of Health	Public	Public health scientist	Ecological and epidemiological surveillance for tick- and mosquito-borne diseases
Hayley Yaglom, MS, MPH, One Health Genomic Epidemiologist, Translational Genomics Research Institute	Public	Scientist	Surveillance, response, and prevention activities for vector-borne and zoonotic diseases at the human-animal (or human-bug) interface
Karen Bloch, MD, MPH, FIDSA, FACP, Associate Professor of Medicine (Infectious Disease) and Health Policy, Vanderbilt University Medical Center	Public	Physician	Infections of the central nervous system and arthropod-borne infections
Vance Fowler, MD, Professor of Medicine, Duke University	Public	Physician	Infectious disease specialist
Christopher D. Paddock, MD, MPHTM, Rickettsial Zoonoses Branch, Centers for Disease Control and Prevention (CDC)	Federal	Scientist and physician	Clinical, epidemiological, and ecological characteristics of tick-borne rickettsioses
Lucas Blanton, MD, Assistant Professor, Department of Internal Medicine, University of Texas Medical Branch at Galveston	Public	Physician and researcher	Infectious disease specialist
Christina M. Farris,* PhD, Viral and Rickettsial Diseases Department, Naval Medical Research Center	Federal	Scientist	Viral and rickettsial diseases
Tony Galbo	Public	Patient advocate	Patient perspectives and advocacy
James Berger, Public Health Policy Advisor, Office of Infectious Disease and HIV/AIDS Policy, Office of the Assistant Secretary for Health, HHS	Federal	Designated Federal Officer for the Working Group	Public Health Policy

*: Due to increased responsibility at work, Christina Farris withdrew her subcommittee membership prior to the subcommittee's 8^th conference call. She participated in previous subcommittee conference calls and discussions.

Subcommittee Meetings

The Subcommittee held a series of weekly/biweekly, one-hour long conference calls in 2019. During the conference calls, subcommittee members shared their expertise through presentations and discussions. Member attendance and topics discussed during the conference calls are summarized in Table 2. Support science writers summarized the conference calls for final edits by the Co-Chairs. Meeting summaries edited and approved by the Co-Chairs are saved on the Subcommittee's SharePoint site for subcommittee members to view and use as references. The presentations were focused on education for physicians (medical students, residents, and clinicians in practice) and other health care providers, surveillance and epidemiology, approaches to clinical diagnosis, and laboratory diagnostics (Table 3).

Table 2: Overview of Rickettsiosis Subcommittee Meetings, 2019

Meeting No.	Date	Attendees	Topics Addressed
1	July 16	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) CDR Todd Myers (alternate to CAPT Estella Jones) Lucas Blanton Karen Bloch Christina Farris Vance Fowler Tony Galbo Christopher Paddock Hayley Yaglom Jennifer Gillissen (Contractor Support) Cat Thomason (Support Writer)	Member introduction Discussion of potential speakers and strategies to accomplish the subcommittee's goals Discussion of potential speakers and strategies to accomplish the subcommittee's goals
2	July 30	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) Karen Bloch Christina Farris David Gaines Tony Galbo Christopher Paddock Hayley Yaglom James Berger (Designated Federal Officer) Jennifer Gillissen (Contractor Support) Christina Li (Support Writer)	Plans for upcoming meetings Presentation on the spectrum of severity of rickettsial infections
3	August 3	CDR Todd Myers Lucas Blanton Christina Farris Vance Fowler David Gaines Hayley Yaglom James Berger (Designated Federal Officer) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Presentation on education and rickettsial diseases Gaps and evidence Problem areas that could potentially be addressed through education
4	August 27	David Walker (Co-Chair) Lucas Blanton Karen Bloch Vance Fowler David Gaines Tony Galbo Christopher Paddock Hayley Yaglom Melinda T Hough (Support Writer)	Surveillance and epidemiology of rickettsial diseases Disease characteristics and clinical limitations Diagnostic and surveillance challenges
5	September 10	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) Lucas Blanton Karen Bloch Vance G. Fowler David Gaines Tony Galbo Christopher Paddock Hayley Yaglom James Berger (Designated Federal Officer) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Clinicians' perspectives on the treatment of spotted fever rickettsioses Strategies for increasing awareness of tick-borne diseases
6	September 24	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) Lucas Blanton Christina Farris David Gaines Tony Galbo Christopher Paddock James Berger (Designated Federal Officer) Yanni Wang (Support Writer)	Laboratory diagnostics for tick-borne spotted fever rickettsiae Subcommittee deliverables: the draft Background and Methods sections
7	October 8	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) Lucas Blanton Karen Bloch Vance Fowler David Gaines Tony Galbo Christopher Paddock Hayley Yaglom James Berger (Designated Federal Officer) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review and discussion of presentation highlights and possible actions developed by David Walker, Karen Bloch, and Vance Fowler Announcement that Christina Farris has withdrawn her subcommittee membership due to increased responsibility at work
8	October 22	David Walker (Co-Chair) CDR Todd Myers (alternate for CAPT Estella Jones) Lucas Blanton Karen Bloch David Gaines Tony Galbo Christopher Paddock Hayley Yaglom Debbie Seem (OIDP, OASH) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review and discussion of presentation summaries and possible actions provided by Hayley Yaglom, Christopher Paddock, and David Gaines Plans for completing and submitting the draft Results and Possible Actions section
9	November 5	David Walker (Co-Chair) CDR Todd Myers (alternate for CAPT Estella Jones) Lucas Blanton Karen Bloch David Gaines Tony Galbo Christopher Paddock Debbie Seem (OIDP, OASH) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review and discussion of the draft Results and Possible Actions section of the Subcommittee report Plans for filling in the gaps and revising the draft Results and Possible Actions section
10	November 19	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) Lucas Blanton Karen Bloch David Gaines Tony Galbo Christopher Paddock Hayley Yaglom James Berger Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review of timeline Review and discussion of the overview and Priorities 1 and 2 of the Results section Discussion of priorities
11	December 3	David Walker (Co-Chair) CDR Todd Myers (alternate for CAPT Estella Jones) Lucas Blanton Karen Bloch Vance Fowler David Gaines Tony Galbo Christopher Paddock James Berger (Designated Federal Officer) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review and discussion of Priorities 3 and 4 of the Results section Discussion of and strategies for prioritizing the possible actions for the Working Group to consider Plans for the next steps
12	December 17	David Walker (Co-Chair) CAPT Estella Jones (Co-Chair) CDR Todd Myers Lucas Blanton Karen Bloch David Gaines Tony Galbo Hayley Yaglom James Berger (DFO) Jennifer Gillissen (Contractor Support) Yanni Wang (Support Writer)	Review and discussion of the draft Subcommittee Report to the Working Group Discussion, revision, and finalization of the Possible Actions for the Working Group to consider Vote on the priorities and revised Possible Actions Plans for final review and revision prior to submission

Table 3: Presenters to the Rickettsiosis Subcommittee

Meeting No.	Presenters	Topics Discussed
2	David Walker	Spectrum of the severity of rickettsial infections
3	Lucas Blanton	Education and rickettsial diseases: deficits in physician knowledge, underlying factors, and potential methods to fill gaps
4	Hayley Yaglom David Gaines Christopher Paddock	Epidemiology of Rocky Mountain spotted fever Tick species associated with transmission of spotted fever group Rickettsia agents to people in North America Diagnostic and surveillance challenges
5	Karen Bloch Vance Fowler	Recognition and empiric treatment of spotted fever rickettsioses: barriers and opportunities Hiding in plain sight: increasing awareness for tick-borne diseases
6	David Walker	Laboratory diagnostics for tick-borne spotted fever rickettsioses
7	David Walker Karen Bloch Vance Fowler	Highlights of presentations and possible actions for the Working Group to consider
8	Hayley Yaglom Christopher Paddock Lucas Blanton Davide Gaines	Highlights of presentations and possible actions for the Working Group to consider

Subcommittee Report Development

The Rickettsiosis Subcommittee developed its report to the Tick-Borne Disease Working Group based on the presentations and subcommittee discussions. Subcommittee Co-Chair David Walker wrote the Background section, drafted the Overview of Rickettsial Diseases in the Results and Possible Actions section, and proposed possible actions for the Working Group to consider. Dr. David Leiby, Center for Biologics Evaluation and Research, FDA, helped develop the Methods section. Other subcommittee members wrote different parts of the Results and Possible Actions section and proposed possible actions for the Working Group to consider: Karen Bloch and Vance Fowler wrote the part on clinical management of spotted fever rickettsial infections, Lucas Blanton wrote the section on education, Hayley Yaglom and Christopher Paddock wrote the section on surveillance and epidemiology, David Gaines developed the part on North American tick species and associated rickettsial agents. Co-Chair David Walker reviewed and edited all parts of the Results and Possible Actions section of the report and distributed them to the subcommittee members for them to review, discuss, and reach consensus.

The subcommittee members reviewed and discussed the draft Results and Possible Actions section, consolidated possible actions to avoid redundancy, and revised the wording of each possible action for accuracy and consistency during the conference calls. The subcommittee members used the PICK CHART to rank the final list of possible actions between December 10 and December 17 conference calls. Different views were addressed via open discussion. During the December 17, 2019 conference call, the Subcommittee reviewed and discussed the revised list of possible actions for the Working Group to consider, consolidated and revised the wordings of the possible actions, and voted to accept the priorities and the final list of possible actions. After the December 17, 2019 conference call, the subcommittee members reviewed, revised, and finalized the subcommittee report together via email. On January 10, 2020, the subcommittee members voted via email to approve the final report to the Working Group. Votes for the possible actions, the priority/topic areas, and the final subcommittee report to the Working Group are captured in Table 4.

Table 4: Votes Taken by the Rickettsiosis Subcommittee

Meeting No. (Date)	Motion	Result	Minority Response
12 (December 17, 2019)*	Accept the four priorities included in the Subcommittee Report	All subcommittee members in attendance (6) unanimously voted yet to accept the priorities	No
12 (December 17, 2019)	Accept the final three possible actions for the Working Group to consider	All subcommittee members in attendance (7) unanimously voted yet to accept the possible actions	No
January 10, 2020	Accept the final subcommittee report to the Working Group	Eight (8) subcommittee members voted yes to accept the final report; one (1) member was absent	No

*: Seven members were present during the first half of the meeting, and eight members were present at the second half of the meeting.

Brief for the Working Group

The Rickettsiosis Subcommittee developed its PowerPoint briefings for the Working Group based on the existing issues, gaps, and opportunities identified; and the priorities and possible actions voted on and accepted by the subcommittee members.

Results and Possible Actions

Overview of Rickettsial Diseases

There are six species of Rickettsia that are potentially transmitted by ticks in the U.S.: R. rickettsii transmitted by Dermacentor variabilis (American dog tick), D. andersoni (Rocky Mountain wood tick), D. occidentalis (the Pacific Coast tick), Rhipicephalus sanguineus sensu lato (brown dog tick), and potentially by Amblyomma americanum (the lone star tick); R. parkeri transmitted by Amblyomma maculatum sensu stricto and sensu lato (Gulf Coast ticks), and potentially by A. americanum and D. parumapertus; Rickettsia 364D transmitted by D. occidentalis (Pacific Coast ticks); and potentially R. massiliae transmitted by R. sanguineus; R. amblyommatis transmitted by A. americanum; and R. prowazekii transmitted by A. tenellum.

Issues

• Rickettsial diseases have undifferentiated signs and symptoms, and variable spectrum of severity, which often make them difficult to distinguish from other infections.
• Awareness of rickettsial diseases by physicians is low.
• The current diagnostic tests for rickettsioses have many limitations.

Evidence and Findings

The spectrum of rickettsial illnesses ranges from life-threatening to asymptomatic (Parola et al., 2013; Walker, Paddock, & Dumler, 2008). The most severe disease, Rocky Mountain spotted fever, is caused by R. rickettsii. The clinical diagnosis of Rocky Mountain spotted fever is hampered by a delay in the appearance of the rash for several days after onset of fever (Helmick, Bernard, & D'Angelo, 1984; Kaplowitz, Fischer, & Sparling, 1981). In addition, those with Rocky Mountain spotted fever may have symptoms that mimic a variety of other syndromes: gastrointestinal symptoms may resemble gastroenteritis or an acute surgical abdomen (Middleton, 1978), pulmonary manifestations may mimic pneumonitis (Donohue, 1980), and neurologic involvement may mimic meningoencephalitis by other causative infectious agents (Rosenblum, Masland, & Harrell, 1952). Finally, inconsistent history of tick exposure may dissuade a physician from considering Rocky Mountain spotted fever as a diagnostic possibility.

In addition to R. rickettsii, other spotted fever group rickettsiae also cause disease in the U.S. (Paddock et al., 2004; Shapiro et al., 2010). However, few physicians recognize the diseases caused by these agents. For example, the diagnosis of R. parkeri infection is hampered by low awareness of the disease and a lack of understanding of the existence and significance of an eschar, the usefulness of the eschar as a site for collection of diagnostic samples for molecular pathogen detection and identification by polymerase chain reaction (PCR), as well as the importance and availability of molecular tests for this disease (Kelman et al., 2018; Myers et al., 2013).

There are many limitations regarding the current diagnostic tests available to physicians (Fang, Blanton, & Walker, 2017). Currently, there are no rapid point-of-care diagnostic testing methods to ensure the accurate diagnosis of a rickettsial disease during early illness. The serologic detection of anti-rickettsial antibodies is the mainstay of laboratory testing, but detectable antibodies are generally not present in the first week of illness when patients first seek evaluation (Biggs et al., 2016). The constellation of significance of the prevalence of anti-spotted fever group rickettsial antibodies in healthy persons in the lone star tick region (McCall et al., 2001; Sanchez et al., 1992; Yevich et al., 1995), the tremendous exposure to R. amblyommatis-carrying lone star ticks (Apperson et al., 2008; Moncayo et al., 2010; Stromdahl, Vince, Billingsley, Dobbs, & Williamson, 2008), the preponderance of single sample serologic testing, and the excessive use of improper or non-quantitative serologic diagnostic assays confounds the accurate diagnosis of acute spotted fever group rickettsial infections (Dahlgren, Paddock, Springer, Eisen, & Behravesh, 2016).

Threats and Challenges

• Life-threatening nature of Rocky Mountain spotted fever.
• Difficulty of diagnosis based on clinical manifestations and epidemiological circumstances at the time of presentation for medical attention.
• Lack of awareness, knowledge, and consideration of the diagnosis of tick-borne rickettsial diseases by primary care and emergency medicine physicians of patients who are in the early phase of a rickettsial infection when treatment is most effective.
• Lack of accurate knowledge of the true regional incidence and epidemiology of tick-borne rickettsioses.
• Lack of a sensitive and specific diagnostic test that is effective early in the course of a rickettsial infection.
• Inability of current serologic tests to identify the specific Rickettsia infecting the patient and to determine whether the antibodies detected are pre-existing or acutely produced.
• Inadequate education of medical students, residents, and practicing physicians regarding rickettsial infections.
• Lack of knowledge regarding rickettsial infections by the general public.
• Improper use and misinterpretation of diagnostic assays that can lead to substantial costs, both economically and to the health of the patient for whom the true cause of the illness may remain undiagnosed.

Opportunities

• Establish educational programs to enhance awareness of and knowledge about rickettsial infections by primary care and emergency physicians and advanced practice medical professionals to improve early initiation of doxycycline treatment and apply the most appropriate laboratory methods to confirm the diagnosis.
• Develop sensitive, specific, point-of-care tests for diagnosis of rickettsial infections early in the clinical course.
• Develop serologic tests that are Rickettsia species-specific and can distinguish pre-existing antibodies from acutely produced antibodies.
• Improve case reporting systems that provide more accurate data on the incidence, specific etiology, and geographic distributions of rickettsial infections.
• Conduct public health information campaigns to increase public awareness of tick-borne rickettsial infections.
• Develop regional tick and tick-borne pathogen surveillance programs to identify public health risks before, rather than after, a person acquires a tick-borne disease.

Possible Actions for the Working Group to Consider

• Establish and fund a research program to develop sensitive and specific point-of-care tests that improve the availability of and access to species-specific assays for acute Rocky Mountain spotted fever and parkeri rickettsiosis; and establish serologic assays that distinguish between antibodies to R. rickettsii, R. parkeri, R. 364D, and R. amblyommatis.

Votes of Subcommittee Members

The possible action was presented and discussed by subcommittee members. The wording of the possible action listed above was voted on by subcommittee members and the result is presented here.

Vote: The subcommittee unanimously voted yes to accept the possible action.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	2

Priority 1: Clinical Management of Spotted Fever Rickettsial Infections

Summary

Delayed initiation of treatment for Rocky Mountain spotted fever and other spotted fever rickettsial infection is associated with adverse outcomes, including increased rates of hospitalization, intensive care unit admission, and mortality. Multiple studies indicate that the most important factor in failure to prescribe empiric doxycycline is not a delay in seeking health care, but rather a failure of providers to consider the diagnosis of spotted fever rickettsial infection, particularly during the first few days of illness when empiric therapy is most effective at reducing morbidity or mortality attributable to these diseases.

Issue

Failure on the part of clinicians to consider the diagnosis, recognize the signs and symptoms, and initiate empiric doxycycline in patients with Rocky Mountain spotted fever and other spotted fever rickettsial infections.

Evidence and Findings

Varied epidemiology

• The highest incidence of human infection with spotted fever group agents occurs in the so-called Rocky Mountain spotted fever belt, extending from North Carolina to Oklahoma. However, sporadic cases of spotted fever rickettsioses occur throughout the continental U.S., and clinicians in areas of low endemicity may be less familiar with the presentation.
• About 90% of reported cases of spotted fever rickettsioses have onset between April and September; however, infection can occur year-round, especially in sites of emerging endemicity such as Arizona.
• A history of tick exposure is not universally present, and absence of this should not dissuade providers from considering a diagnosis of a spotted fever rickettsiosis.

Diverse clinical presentations

• The earliest symptoms of spotted fever rickettsioses are nonspecific, consisting of fever, headache, and myalgias. Laboratory abnormalities are typically undetectable at this stage.
• By days 2 to 4 of illness, approximately 50% of patients will have developed a rash (macular lesions around ankles and wrists), which is often subtle at this stage. Laboratory findings suggestive of the diagnosis such as thrombocytopenia and elevated liver enzymes may be present.
• By days 5 to 7, the fever and constitutional symptoms persist, the rash becomes petechial and generalized, and laboratory abnormalities become more pronounced.
• If left untreated, after 5 days of symptoms, life-threatening complications can occur, such as sepsis, meningoencephalitis, purpura fulminans, renal insufficiency, acute respiratory distress syndrome, or other devastating complications of this infection.
• The mortality rate in the absence of treatment exceeds 20% for Rocky Mountain spotted fever, and sequelae such as cognitive impairment, seizures, renal dysfunction, and limb amputation may be seen among survivors.
• Atypical presentations (for example, enteric symptoms and meningoencephalitis) are not infrequent, and providers may consider alternative diagnoses when focal symptoms predominate.

Knowledge gaps

• Provider surveys have demonstrated striking disparities in first choice of treatment for Rocky Mountain spotted fever in children. While 69-93% of providers surveyed responded that they would give doxycycline to adults and children older than 8 years of age, only 30-51% of providers surveyed would use doxycycline in children 8 years of age or younger.
• There is an ongoing, misplaced concern that even short courses of doxycycline could stain permanent teeth of young children, despite consistent and strong messaging from CDC and the American Academy of Pediatrics stating that doxycycline is safe for all ages and is the recommended therapy for rickettsial infections in patients of all ages.

Opportunities

• Improve provider recognition and empiric treatment of Rocky Mountain spotted fever/spotted fever rickettsioses at early stages of the illness (for example, prior to the onset of a rash).
• Educate providers on updated recommendations for using doxycycline in children younger than 8 years of age.

Challenges

• Mandated training modules that indiscriminately target clinicians who do not provide primary care or urgent care may be challenging to implement.
• Overly-broad training materials that emphasize different aspects of tick-borne illnesses that are not relevant to the recognition and treatment of infection (for example, epidemiology, entomology, or retrospective diagnostics) may produce low yield results.

Possible Actions for the Working Group to Consider

• Fund an educational outreach effort across the U.S. with mandatory rickettsial diseases continuing medical education to inform first-line responders (primary care physicians, advanced practice providers, pediatricians, urgent care providers, and emergency department providers) about the best diagnostic assays to use, best diagnostic samples to collect, and best strategies for treating patients (with a focus on doxycycline) when they are diagnosed with or suspected of having Rocky Mountain spotted fever or another tick-borne rickettsiosis.
  1. Fund seasonal educational outreach efforts in endemic regions to raise public awareness about rickettsial diseases.
  2. Encourage accrediting bodies to ensure education on tick-borne diseases in medical school curricula and graduate medical education, and recommend that there be a greater presence of tick-borne disease material on licensing examinations and specialty board examinations.

Votes of Subcommittee Members

The possible action was presented and discussed by subcommittee members. The wording of the possible action listed above was voted on by subcommittee members and the result is presented here.

Vote: The subcommittee unanimously voted yes to accept the possible action.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	2

Priority 2: Education on Rickettsial Diseases

Summary

Severe manifestations, sequelae, and death attributed to Rocky Mountain spotted fever can be avoided with the initiation of doxycycline during the first few days of illness (Kirkland, Wilkinson, & Sexton, 1995). Unfortunately, the difficulty of recognizing the disease clinically, misconceptions that erroneously anchor physician beliefs regarding side effects of doxycycline, failure to recognize the severity of the disease, and misconceptions regarding laboratory testing often lead to the failure of prescribing appropriate antimicrobial therapy (Alvarez-Hernandez, Ernst, Acuna-Melendrez, Vargas-Ortega, & Candia-Plata, 2018; Mosites et al., 2013; Zientek, Dahlgren, McQuiston, & Regan, 2014). Even for less severe rickettsial infections, such as those caused by R. parkeri, failure to recognize and treat can lead to an unnecessarily prolonged febrile illness (Paddock et al., 2008). Many factors may contribute to the failure to recognize the disease and misconceptions regarding its treatment. These include busy clinical practices and the growing complexity of medicine, which all compete for physicians' time. In addition, waning knowledge of less prevalent diseases (for example, Rocky Mountain spotted fever), compared with knowledge of more common illnesses, may also play a role. Although the clinical practice patterns that contribute to the failure to recognize Rocky Mountain spotted fever are challenging to change, the issues that contribute to the failure of timely prescribing doxycycline can be addressed through enhanced educational efforts. Opportunities exist at all levels of education, training, and practice.

Issue

The failure to clinically recognize Rocky Mountain spotted fever as a possible diagnosis and misconceptions regarding the timing/appropriateness of doxycycline therapy can lead to severe illness and death.

Evidence and Findings

Evidence that gaps in knowledge exist

Studies of physician knowledge regarding Rocky Mountain spotted fever have revealed the following (Alvarez-Hernandez et al., 2018; Mosites et al., 2013; Zientek et al., 2014).

• Physicians often fail to recognize that doxycycline should be initiated prior to the results of laboratory testing.
• Many physicians would not consider the diagnosis in the absence of a rash.
• Physicians often fail to recognize that doxycycline is the treatment of choice for children.
• Physicians often fail to recognize death as a potential outcome of Rocky Mountain spotted fever, and that the disease can progress to death within a week of illness onset.

Challenges

Reasons that gaps exist in clinician knowledge

• Medical school curricula must prepare students with a wide range of materials over a short period of time. Rapid advances in all fields of medicine have led to increasing specialization.
• During residency, physicians in training often have massive and hectic workloads. For infections that vary regionally, physicians training in one part of the country may not be able obtain clinical experiences that could optimally prepare them for practicing in a different region.
• Clinicians in practice are extremely busy. They often have little time to gather the necessary clinical information and formulate a plan of care for diseases, which may contribute to missing an important diagnosis. Those on the front line of care (for example, primary care physicians and emergency medicine physicians) often deal with a great variety of medical problems, and may not readily distinguish rickettsial infections from the variety of alternative causes of fever, rash, and headache.

Opportunities

Problem areas that could potentially be addressed through education

• The signs and symptoms of rickettsial diseases are largely undifferentiated during the early stages of illness and mimic a variety of other infectious syndromes. Therefore, it can be difficult for physicians to recognize the illness (Biggs et al., 2016).
• It is important for practitioners to realize that a rash, which is frequently considered a characteristic for a rickettsiosis, is often absent during the early stages of the illness (Helmick et al., 1984; Kaplowitz et al., 1981).
• Unfortunately, there are no rapid point-of-care diagnostic tests available to accurately diagnose rickettsioses (Fang, Blanton, & Walker, 2017). Antibodies reactive to rickettsial antigens are not present during the early stages of the illness (Paris & Dumler, 2016). It is important to recognize that treatment should not wait for results of laboratory testing (Kirkland et al., 1995).
• Although most clinicians recognize that doxycycline is the treatment of choice for rickettsial diseases, some are often hesitant to prescribe it, especially for children (Alvarez-Hernandez et al., 2018; Mosites et al., 2013; Zientek et al., 2014) and during pregnancy (Cross, Ling, Day, McGready, & Paris, 2016).

Possible Actions for the Working Group to Consider

• Fund an educational outreach effort across the U.S. with mandatory rickettsial diseases continuing medical education to inform first-line responders (primary care physicians, advanced practice providers, pediatricians, urgent care providers, and emergency department providers) about the best diagnostic assays to use, best diagnostic samples to collect, and best strategies for treating patients (with a focus on doxycycline) diagnosed with or suspected of having Rocky Mountain spotted fever or another tick-borne rickettsiosis.
  1. Fund seasonal educational outreach efforts in endemic regions to raise public awareness about rickettsial diseases.
  2. Encourage accrediting bodies to ensure tick-borne diseases education in medical school curricula and graduate medical education and recommend that there be a greater presence of tick-borne disease material on licensing examinations and specialty board examinations.

Votes of Subcommittee Members

The possible action was presented and discussed by subcommittee members. The wording of the possible action listed above was voted on by subcommittee members and the result is presented here.

Vote: The subcommittee unanimously voted yes to accept the possible action.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	2

Priority 3: Surveillance and Epidemiology

Summary

Rocky Mountain spotted fever remains the most severe tick-borne rickettsial illness and has been a nationally notifiable condition since the early 1920s. In 2010, the reportable diseases list was updated to capture two additional tick-borne spotted fever rickettsioses discovered during the first decade of the 21st century (R. parkeri rickettsiosis and Pacific Coast tick fever caused by Rickettsia 364D). These three diseases are now included collectively as nationally notifiable conditions under the general heading of "spotted fever rickettsiosis."

Issues

Because national surveillance for spotted fever rickettsiosis is based exclusively on passive reporting of cases that are largely confirmed by non-specific serologic tests that often detect background seroprevalence rather than confirm an active disease, these data are unlikely to accurately describe the magnitude of these diseases or identify the specific agent responsible for the actual illness. In this context, existing surveillance is susceptible to under and over representation. It is important to determine more accurately the true contribution of undetected or under-detected spotted fever group rickettsial pathogens, and the contribution caused by remote exposures to nonpathogenic or possibly minimally pathogenic agents such as R. amblyommatis, R. montanensis, or R. andeanae that result in non-specific background seroprevalence.

Evidence and Findings

The number of cases of spotted fever group rickettsioses reported to the Centers for Disease Control and Prevention per year has increased significantly during the last two decades. While 495 cases were reported in 2000, more than 6,200 cases were reported in 2017 (Heitman et al., 2019).

Factors that complicate surveillance include the following.

• Approximately 82% of all cases identified by national surveillance are identified by a single antibody titer to spotted fever group Rickettsia determined by indirect immunofluorescence antibody assays (IFA) (Binder, Heitman, & Drexler, 2019).
• Baseline seropositivity to spotted fever group Rickettsiae in healthy blood donors is as high as 11% in some areas of the U.S. (Straily et al., 2019).
• Many other spotted fever group Rickettsia species of uncertain pathogenicity are found in North America's human-biting ticks and could elicit cross-reactive antibodies (Dahlgren et al., 2016).
• Improper interpretation of serologic tests can significantly affect the accuracy of national surveillance data and obscure the recognition of the true etiologic agents of diseases, particularly those caused by other tick-borne pathogens, such as Ehrlichia chaffeensis, Ehrlichia ewingii, Heartland virus, and Bourbon virus (Egizi, Fefferman, & Jordan, 2017; McClain & Sexton, 2019).

Opportunities

The Council of State and Territorial Epidemiologists adopted a revised case definition for spotted fever group rickettsioses in June 2019, most notably by requiring an IgG titer of 128 or greater as serological evidence of a probable case. This represents a two-fold greater antibody titer than required by the previous surveillance case definition. Because approximately 45% of all recently reported cases of spotted fever rickettsioses in the U.S. were based on a single IgG antibody titer of 64 (Nichols Heitman et al, 2019), this change will likely reduce the overdiagnosis, particularly in high incidence states. Nonetheless, recent studies indicate that a single antibody titer is an unreliable measure of diagnosis and could inaccurately affect surveillance estimates that define the magnitude and clinical characteristics of Rocky Mountain spotted fever and other spotted fever rickettsioses (Straily et al 2019).

Challenges

• Cross-reactive antigens of spotted fever group Rickettsia species generally preclude assignment of the specific etiologic agent using current serological methods.
• Relatively small amounts of pathogen nucleic acid are found in circulation during the early stages of illness, making molecular detection particularly challenging during the first few days of disease.
• Appropriate use of the IFA assay requires tandem analysis of sera collected during the acute and convalescent phases of illness. However, convalescent serum specimens are collected and tested infrequently, and only 1% of reported cases of spotted fever are supported by this method.

Possible Actions for the Working Group to Consider

• Fund prospective programs on active clinical and environmental surveillance to understand the true geographic distributions and clinical incidence of rickettsial diseases including programs that survey for changing distributions of medically important tick species and rickettsial pathogens within these species.

Votes of Subcommittee Members

The possible action was presented and discussed by subcommittee members. The wording of the possible action listed above was voted on by subcommittee members and the result is presented here.

Vote: The subcommittee unanimously voted yes to accept the possible action.

Number in Favor	Number Opposed	Number Abstained	Number Absent
7	0	0	2

Priority 4: North American Tick Species Associated with Transmission of Spotted Fever Group Rickettsial Agents to People

Summary

Currently there are six tick species in the U.S. that are most commonly associated with, or suspected of transmitting, pathogenic and/or non-pathogenic spotted fever group rickettsial agents to people. These include three Dermacentor species (D. andersoni, D. variabilis, and D. occidentalis), two Amblyomma species (A. americanum and A. maculatum), and one Rhipicephalus species (R. sanguineus). Although these six tick species occur in distinct regions of the U.S., some regions overlap and together they cover most of the U.S.

When Rocky Mountain spotted fever was first discovered in the early 1900s, it was causing up to 50 or more human fatalities per year in the Bitterroot Valley of Montana. The high human fatality rates caused by Rocky Mountain spotted fever at that time, and the association between the disease and recent tick bites led to investigations of local tick species and the discovery of the bacterial agent, R. rickettsii, in D. andersoni ticks collected around the outbreak areas.

After the discovery of Rocky Mountain spotted fever and its association with D. andersoni ticks in the Rocky Mountain region, Rocky Mountain spotted fever transmission was also reported to be associated with American dog ticks (D. variabilis), which occur throughout areas of the Eastern U.S., as well as in certain areas of California. Recently, another Dermacentor species found in California the Pacific Coast tick (D. occidentalis), was identified as a carrier and potential vector of R. rickettsii.

Since the discovery of Rocky Mountain spotted fever, Dermacentor tick species were the primary focus of Rocky Mountain spotted fever surveillance and prevention. However, recent pathogen surveys of Dermacentor ticks have generally found relatively low R. rickettsii infection rates (generally less than 1%) in Dermacentor ticks tested using the molecular laboratory assays such as PCR.

Table 5 summarizes the results of a selection of published molecular surveys for spotted fever group Rickettsia in the six species of ticks currently thought to play roles in the transmission of these rickettsial agents to people. Dergousoff and colleagues (Dergousoff, Gajadhar, & Chilton, 2009) published the only relatively recent molecular survey for rickettsial agents in D. andersoni (the Rocky Mountain wood tick) in a Rocky Mountain region of Canada (just north of Idaho and Montana) and did not detect any pathogenic rickettsial agents among the 508 tested ticks collected from nine different sites. A recent survey of adult D. variabilis ticks collected from multiple U.S. states identified R. rickettsii in only 1 (0.1%) of 883 specimens (Hecht et al., 2019). Another recent D. variabilis survey in North Carolina (Kakumanu et al., 2018) tested 532 adult ticks for eight different spotted fever group agents, and R. rickettsii was detected in only five (0.9%) of the tested ticks. Two other known spotted fever group pathogens, R. parkeri and R. massiliae, were also found in 7.8 and 3.8% of these tested ticks, respectively. R. parkeri and R. massiliae are not known to cause fatal illnesses in people. Spotted fever group agents such as R. amblyommatis and R. montanensis were also detected in 29.3% and 7.7% of the tested D. variabilis, respectively. Although R. amblyommatis and R. montanensis could potentially cause mild symptoms in some people, the symptoms are not well defined (Yoshimizu & Billeter, 2018) and it is likely that the majority of persons exposed to these agents develop no symptoms. Wikswo and colleagues (Wikswo et al., 2008) surveyed D. occidentalis in southern California and found R. rickettsii in 0.3% of 365 collected ticks. Additionally, a newly identified human spotted fever group rickettsial pathogen called Rickettsia 364D was also identified in 7.7% of the 365 collected D. occidentalis. Rickettsia 364D (proposed nomenclature, R. philipii, Table 5) has been determined to be moderately pathogenic to people (Padgett et al., 2016).

Table 5. Six common human-biting tick species involved in the transmission of Rocky Mountain spotted fever and/or other agents of the spotted fever group Rickettsiae in the United States. This table shows the spotted fever group Rickettsia agents and infection rates identified by molecular methods in field-collected ticks and their known human pathogenicity.

Tick Species and Scientific Names	Rocky Mountain wood tick Dermacentor andersoni	American dog tick Dermacentor variabilis	Pacific Coast tick Dermacentor occidentalis	Lone star tick Amblyomma americanum	Gulf Coast tick Amblyomma maculatum	Brown dog tick Rhipicephalus sanguineus
Spotted fever group Rickettsia agents
Rickettsia rickettsii 1	Unknown*	0.9%	0.3%	0%**	0%	0 to 43%
Rickettsia parkeri 2	-	7.8%	-	0.4 to 1%	0 to 51.2%	-
Rickettsia massiliae 2	-	3.8%	-	-	-	25 to 72%
Rickettsia 364D 2	-	-	1.3 to 7.7%	-	-	-
Rickettsia amblyommatis 3	-	29.3%	-	55.9 to 72.8%	-	-
Rickettsia montanensis 3	-	7.7%	-	-	-	-
Rickettsia andeanae 4	-	-	-	-	0.33 to 73%	-
Rickettsia rhipicephali 4	-	0.4%	24.7%	-	-	-
Rickettsia bellii 4	-	1.9%	-	-	-	-
Rickettsia peacockii 4	76%	-	-	-	-	-
Rickettsia conorii-like 5	-	3.5%	-	-	-	-

¹ Severe human pathogen, ² Moderate to mild human pathogen, ³ Mild or non-pathogen, ⁴ No evidence of pathogenicity, ⁵ Unknown

* There have been few published surveys for spotted fever group Rickettsia pathogens in Rocky Mountain wood ticks since the advent of molecular testing methods.

** Although thousands of lone star ticks have been tested for spotted fever group Rickettsia pathogens according to published studies, only a single lone star tick has been reported as carrying R. rickettsii (Breitschwerdt et al., 2011)

Although Dermacentor tick species can be found in many regions of the U.S., most of the more recently diagnosed human Rocky Mountain spotted fever cases have been concentrated in the southeastern U.S. This geographic concentration of cases coincides primarily with the distribution of the lone star tick as well as the Gulf Coast tick. American dog ticks occur throughout the eastern U.S. and occasionally bite people in the southeastern region, but a majority of the tick bites reported by people in the Southeastern region appear to be caused by lone star ticks.

Because Rocky Mountain spotted fever is known to be transmitted to people by several Amblyomma tick species in South America, the two most common Amblyomma species from the southeastern U.S. (A. americanum and A. maculatum) have been studied as potential vectors. Table 5 shows that among various surveys of these two Amblyomma species for spotted fever group rickettsial pathogens, only one single A. americanum tick has been identified as carrying R. rickettsii (Breitschwerdt et al., 2011). No other pathogen survey of Amblyomma tick species in the southeastern U.S. has found R. rickettsii, but several other spotted fever group rickettsial agents have been found in Amblyomma species, including R. parkeri, which was found in up to 51% of the 301 A. maculatum ticks tested in Virginia (Nadolny et al. 2014), and in 29% of the 234 A. maculatum ticks tested in North Carolina (Varela-Stokes et al., 2011). R. parkeri was not found in any of the 226 A. maculatum tested from Oklahoma and Kansas (Paddock et al., 2015). Rickettsia amblyommatis was the most common spotted fever group agent identified in A. americanum ticks tested from across the southeastern U.S., and was found in 55.9% of the 1,381 nymphs and 72% of the 206 adult ticks tested from 24 sites across Virginia (Gaines et al., 2014).

Given the high rates of R. amblyommatis infection in lone star ticks, and the relatively large numbers of people who are bitten by these ticks that do not experience any illness each year, the pathogenic status of R. amblyommatis is questionable. However exposure to any spotted fever group Rickettsia through a tick bite might cause the tick bite victim to subsequently test positive on a serological test for Rocky Mountain spotted fever for up to a year or more after exposure. Therefore, the prevalence of R. amblyommatis and other non-pathogenic, or mildly pathogenic, agents carried by Amblyomma ticks in the southeastern U.S. may explain the very high numbers of Rocky Mountain spotted fever cases diagnosed each year in this region and may mask the occurrence of real RMSF cases.

Since 2004, several large Rocky Mountain spotted fever outbreaks have occurred in human populations in Arizona and northern Mexico. These outbreaks have been determined to have been caused exclusively by bites of the brown dog tick (R. sanguineus). Subsequently, numerous pathogen surveys have been conducted on R. sanguineus populations in the southwestern U.S. and northern Mexico. Some of these studies have detected R. rickettsii in relatively high proportions of the tested R. sanguineus tick population at surveyed sites. For example, in 2019, R. sanguineus collected at multiple survey sites in northern Mexico and Arizona had site-specific infection rates ranging up to 43% (Owen et al., 2019). Additionally, in 2005, one collection of R. sanguineus in the southeastern U.S. state of Georgia detected R. rickettsii in one of the 12 R. sanguineus collected (Garrison et al. 2007). These high infection rates suggest that R. sanguineus is an important vector of Rocky Mountain spotted fever. In addition to R. rickettsii, surveys of R. sanguineus ticks in Arizona, California, and Virginia have found R. massiliae, with tick infection rates of 25% in Arizona (Eremeeva et al., 2011), 72% in California (Beeler et al., 2011), and 33.3% in Virginia (Fornadel, et al., 2013). Although brown dog ticks are uncommon on dogs that are well cared for, they can multiply in association with unmanaged dog populations and/or poorly maintained domestic dogs and domestic dog environments throughout the U.S.

Evidence and Findings

Among the 11 identified spotted fever group Rickettsia agents carried by the six tick species examined in Table 5, four spotted fever group Rickettsia species (R. rickettsii, R. parkeri, R. massiliae, and R. 364D) are proven human pathogens. While R. rickettsii infections are clearly known to cause fatal illnesses in people, the other three agents are not; nonetheless they are of medical concern and need further investigation. Additionally, as the pathogenicity of R. amblyommatis and R. montanensis is poorly supported, more evidence is needed to determine whether these spotted fever group Rickettsiae are human pathogens worthy of concern.

Challenges and Opportunities

Ticks that are suspected of being Rocky Mountain spotted fever vectors to people commonly carry a variety of nonpathogenic, or mildly pathogenic, spotted fever group Rickettsia agents. Infections caused by these common non-pathogenic or mildly pathogenic rickettsial agents may cause positive serologic test results inpatients being tested for Rocky Mountain spotted fever, causing overdiagnosis and overtreatment. The local occurrence of real Rocky Mountain spotted fever outbreaks in regions where R. amblyommatis is common may be obscured because clinicians that have come to expect patients to test positive for RMSF during the acute phase of illness may fail to recognize R. rickettsii infections in acute patients who do not test positive for RMSF. Therefore, the development of agent-specific diagnostic assays for diagnosis of suspected spotted fever group rickettsial illnesses in the acute stage of the illness could help define the actual prevalence of spotted fever rickettsial illnesses, prevent overdiagnosis and overtreatment, and identify serious rickettsial infections when they occur.

Summary

Rocky Mountain spotted fever is one of the most severe infectious diseases with a fatality rate of more than 20% among previously healthy persons, if not treated with an appropriate antibiotic. Adjacent to the U.S. border in Mexico there are hundreds of cases of Rocky Mountain spotted fever caused by an even more virulent strain of R. rickettsii with a fatality rate of 40%, including appropriately treated cases (Alvarez-Hernandez et al., 2017). A similar epidemiologic situation is occurring on Indian tribal lands in Arizona where peridomestic transmission is driven by brown dog ticks. Two additional tick-borne spotted fever rickettsioses have been discovered in recent years, R. parkeri rickettsiosis and Pacific Coast tick fever caused by Rickettsia 364D. Antibodies reactive with R. rickettsii are present in 10-20% of healthy persons, particularly in the widening geographic distribution of the lone star tick (Marshall et al., 2003). The high seroprevalence confounds serologic diagnosis and suggests previous subclinical infections with less virulent Rickettsia. The true incidence and geographic distribution of infections caused by each pathogenic tick-borne Rickettsia is unknown. This situation results from misdiagnosis, failure to utilize appropriate diagnostic assays and correctly interpret the results, lack of general availability of tests that can establish the diagnosis early in the course of illness when therapeutic decisions are made, and lack of a serologic assay that can determine the specific spotted fever group Rickettsia that stimulated the antibodies.

The most important factor contributing to the failure to diagnose and effectively treat tick-borne rickettsioses is a lack of consideration of the potential diagnosis by primary care providers and emergency department physicians in patients presenting with an undifferentiated acute febrile illness during tick season. This situation exists because of insufficient primary and continuing medical education for front line providers, including physician extenders, medical students, primary care and emergency medicine residents, and practicing physicians regarding tick-borne rickettsioses. Delayed initiation of appropriate antibiotics is associated with adverse outcomes including increased rates of hospitalization, admission to an intensive care unit, and mortality. The earliest symptoms are nonspecific, including fever, headache, myalgias, and nausea/or vomiting. Rickettsial infection may not be considered until a rash is apparent, a median of three days after onset of fever. Laboratory abnormalities are typically absent at the initial presentation, further obscuring the diagnosis. There is a mistaken idea among a substantial portion of health care providers that the best antibiotic available, doxycycline, should not be administered to children eight years of age or younger or during pregnancy. Delays in recognizing and treating rickettsial diseases is associated with unnecessary morbidity and mortality. This report proposes measures to address these critical issues regarding tick-borne rickettsioses.

References

Alvarez-Hernandez, G., Ernst, K., Acuna-Melendrez, N. H., Vargas-Ortega, A. P., & Candia-Plata, M. D. C. (2018). Medical knowledge related to Rocky Mountain spotted fever in Sonora, Mexico. Trans R Soc Trop Med Hyg. doi:10.1093/trstmh/try030

Alvarez-Hernandez, G., Roldan, J. F. G., Milan, N. S. H., Lash, R. R., Behravesh, C. B., & Paddock, C. D. (2017). Rocky Mountain spotted fever in Mexico: past, present, and future. Lancet Infect Dis, 17(6), e189-e196. doi:10.1016/S1473-3099(17)30173-1

Beeler, E., Abramowicz, K. F., Zambrano, M. L., Sturgeon, M. M., Khalaf, N., Hu, R., . . . Eremeeva, M. E. (2011). A focus of dogs and Rickettsia massiliae-infected Rhipicephalus sanguineus in California. Am J Trop Med Hyg, 84(2), 244-249. doi:10.4269/ajtmh.2011.10-0355

Biggs, H. M., Behravesh, C. B., Bradley, K. K., Dahlgren, F. S., Drexler, N. A., Dumler, J. S., . . . Traeger, M. S. (2016). Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States. MMWR Recomm Rep, 65(2), 1-44. doi:10.15585/mmwr.rr6502a1

Binder, A. M., Heitman, K. N., & Drexler, N. A. (2019). Diagnostic Methods Used to Classify Confirmed and Probable Cases of Spotted Fever Rickettsioses — United States, 2010–2015. Morbidity and Mortality Weekly Report (MMWR), 68(10), 243-246.

Breitschwerdt, E. B., Hegarty, B. C., Maggi, R. G., Lantos, P. M., Aslett, D. M., & Bradley, J. M. (2011). Rickettsia rickettsii transmission by a lone star tick, North Carolina. Emerg Infect Dis, 17(5), 873-875. doi:10.3201/eid1705.101530

CDC Nationally Notifiable Infectious Diseases and Conditions, United States: Annual Tables. (2018). Retrieved from https://wonder.cdc.gov/nndss/static/2018/annual/2018-table2m.html

Cross, R., Ling, C., Day, N. P., McGready, R., & Paris, D. H. (2016). Revisiting doxycycline in pregnancy and early childhood--time to rebuild its reputation? Expert Opin Drug Saf, 15(3), 367-382. doi:10.1517/14740338.2016.1133584

Dahlgren, F. S., Paddock, C. D., Springer, Y. P., Eisen, R. J., & Behravesh, C. B. (2016). Expanding Range of Amblyomma americanum and Simultaneous Changes in the Epidemiology of Spotted Fever Group Rickettsiosis in the United States. Am J Trop Med Hyg, 94(1), 35-42. doi:10.4269/ajtmh.15-0580

Dergousoff, S. J., Gajadhar, A. J., & Chilton, N. B. (2009). Prevalence of Rickettsia species in Canadian populations of Dermacentor andersoni and D. variabilis. Appl Environ Microbiol, 75(6), 1786-1789. doi:10.1128/AEM.02554-08

Donohue, J. F. (1980). Lower respiratory tract involvement in Rocky Mountain spotted fever. Arch Intern Med, 140(2), 223-227.

Egizi, A., Fefferman, N. H., & Jordan, R. A. (2017). Relative Risk for Ehrlichiosis and Lyme Disease in an Area Where Vectors for Both Are Sympatric, New Jersey, USA. Emerg Infect Dis, 23(6). doi:10.3201/eid2306.160528

Eremeeva, M. E., Zambrano, M. L., Anaya, L., Beati, L., Karpathy, S. E., Santos-Silva, M. M., . . . Aranda, C. A. (2011). Rickettsia rickettsii in Rhipicephalus ticks, Mexicali, Mexico. J Med Entomol, 48(2), 418-421. doi:10.1603/me10181

Fang, R., Blanton, L. S., & Walker, D. H. (2017). Rickettsiae as Emerging Infectious Agents. Clin Lab Med, 37(2), 383-400. doi:10.1016/j.cll.2017.01.009

Fornadel, C. M., Smith, J. D., Zawada, S. E., Arias, J. R., & Norris, D. E. (2013). Detection of Rickettsia massiliae in Rhipicephalus sanguineus from the eastern United States. Vector Borne Zoonotic Dis, 13(1), 67-69. doi:10.1089/vbz.2012.1058

Gaines, D. N., Operario, D. J., Stroup, S., Stromdahl, E., Wright, C., Gaff, H., . . . Houpt, E. (2014). Ehrlichia and spotted fever group Rickettsiae surveillance in Amblyomma americanum in Virginia through use of a novel six-plex real-time PCR assay. Vector Borne Zoonotic Dis, 14(5), 307-316. doi:10.1089/vbz.2013.1509

Garrison, L. E., Kelly, R., Nicholson, W. L., & Eremeeva, M. E. (2007). Tick Surveillance Notes: Rickettsia rickettsii in Rhipicephalus sanguineus Ticks from Gordon County. Georgia Epidemiology Report, 23(4), 3.

Hecht, J. A., Allerdice, M. E. J., Dykstra, E. A., Mastel, L., Eisen, R. J., Johnson, T. L., . . . Karpathy, S. E. (2019). Multistate Survey of American Dog Ticks (Dermacentor variabilis) for Rickettsia Species. Vector Borne Zoonotic Dis, 19(9), 652-657. doi:10.1089/vbz.2018.2415

Heitman, K. N., Drexler, N. A., Cherry-Brown, D., Peterson, A. E., Armstrong, P. A., & Kersh, G. J. (2019). National Surveillance Data Show Increase in Spotted Fever Rickettsiosis: United States, 2016-2017. Am J Public Health, 109(5), 719-721. doi:10.2105/AJPH.2019.305038

Helmick, C. G., Bernard, K. W., & D'Angelo, L. J. (1984). Rocky Mountain spotted fever: clinical, laboratory, and epidemiological features of 262 cases. J Infect Dis, 150(4), 480-488. doi:10.1093/infdis/150.4.480

Kakumanu, M. L., Ponnusamy, L., Sutton, H., Meshnick, S. R., Nicholson, W. L., & Apperson, C. S. (2018). Prevalence of Rickettsia Species (Rickettsiales: Rickettsiaceae) in Dermacentor variabilis Ticks (Acari: Ixodidae) in North Carolina. J Med Entomol, 55(5), 1284-1291. doi:10.1093/jme/tjy074

Kaplowitz, L. G., Fischer, J. J., & Sparling, P. F. (1981). Rocky Mountain spotted fever:  A clinical dilemma. In J. B. Remington & H. N. Swartz (Eds.), Current Clinical Topics in Infectious Diseases (Vol. 2, pp. 89-108). New York: McGraw-Hill.

Kelman, P., Thompson, C. W., Hynes, W., Bergman, C., Lenahan, C., Brenner, J. S., . . . Gaff, H. (2018). Rickettsia parkeri infections diagnosed by eschar biopsy, Virginia, USA. Infection. doi:10.1007/s15010-018-1120-x

Kirkland, K. B., Wilkinson, W. E., & Sexton, D. J. (1995). Therapeutic delay and mortality in cases of Rocky Mountain spotted fever. Clin Infect Dis, 20(5), 1118-1121.

Marshall, G. S., Stout, G. G., Jacobs, R. F., Schutze, G. E., Paxton, H., Buckingham, S. C., . . . Woods, C. R. (2003). Antibodies reactive to Rickettsia rickettsii among children living in the southeast and south central regions of hte United States. Arch Pediatr Adolesc Med, 157, 443-448.

McCall, C. L., Curns, A. T., Rotz, L. D., Singleton, J. A., Jr., Treadwell, T. A., Comer, J. A., . . . Childs, J. E. (2001). Fort Chaffee revisited: the epidemiology of tick-borne rickettsial and ehrlichial diseases at a natural focus. Vector Borne Zoonotic Dis, 1(2), 119-127. doi:10.1089/153036601316977723

McClain, M. T., & Sexton, D. J. (2019). Surveillance for Spotted Fever Group Rickettsial Infections: Problems, Pitfalls and Potential Solutions. J Infect Dis. doi:10.1093/infdis/jiz317

Middleton, D. B. (1978). Rocky Mountain spotted fever: gastrointestinal and laboratory manifestations. South Med J, 71(6), 629-632. doi:10.1097/00007611-197806000-00007

Mosites, E., Carpenter, L. R., McElroy, K., Lancaster, M. J., Ngo, T. H., McQuiston, J., . . . Dunn, J. R. (2013). Knowledge, attitudes, and practices regarding Rocky Mountain spotted fever among healthcare providers, Tennessee, 2009. Am J Trop Med Hyg, 88(1), 162-166. doi:10.4269/ajtmh.2012.12-0126

ajtmh.2012.12-0126 [pii]

Myers, T., Lalani, T., Dent, M., Jiang, J., Daly, P. L., Maguire, J. D., & Richards, A. L. (2013). Detecting Rickettsia parkeri infection from eschar swab specimens. Emerg Infect Dis, 19(5), 778-780. doi:10.3201/eid1905.120622

Nadolny, R. M., Wright, C. L., Sonenshine, D. E., Hynes, W. L., & Gaff, H. D. (2014). Ticks and spotted fever group rickettsiae of southeastern Virginia. Ticks Tick Borne Dis, 5(1), 53-57. doi:10.1016/j.ttbdis.2013.09.001

Owen, H., Lisowski, S., Schaefer, C., Yao, T., Allen, J., Goetz, N., . . . VandenBrooks, J. (2019). Variation in the Geographic Distribution and Rickettsial infection Rates of Rhipicephalus sanguineus Contributes to the Spread of RMSF In Arizona and Mexico. The FASEB Journal, 33(No.1_supplement).

Paddock, C. D., Denison, A. M., Dryden, M. W., Noden, B. H., Lash, R. R., Abdelghani, S. S., . . . Little, S. E. (2015). High prevalence of "Candidatus Rickettsia andeanae" and apparent exclusion of Rickettsia parkeri in adult Amblyomma maculatum (Acari: Ixodidae) from Kansas and Oklahoma. Ticks Tick Borne Dis, 6(3), 297-302. doi:10.1016/j.ttbdis.2015.02.001

Paddock, C. D., Finley, R. W., Wright, C. S., Robinson, H. N., Schrodt, B. J., Lane, C. C., . . . Eremeeva, M. E. (2008). Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Clin Infect Dis, 47(9), 1188-1196. doi:10.1086/592254

Paddock, C. D., Sumner, J. W., Comer, J. A., Zaki, S. R., Goldsmith, C. S., Goddard, J., . . . Ohl, C. A. (2004). Rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infect Dis, 38(6), 805-811. doi:10.1086/381894

Padgett, K. A., Bonilla, D., Eremeeva, M. E., Glaser, C., Lane, R. S., Porse, C. C., . . . Kramer, V. (2016). The Eco-epidemiology of Pacific Coast Tick Fever in California. PLoS Negl Trop Dis, 10(10), e0005020. doi:10.1371/journal.pntd.0005020

Paris, D. H., & Dumler, J. S. (2016). State of the art of diagnosis of rickettsial diseases: the use of blood specimens for diagnosis of scrub typhus, spotted fever group rickettsiosis, and murine typhus. Curr Opin Infect Dis, 29(5), 433-439. doi:10.1097/QCO.0000000000000298

Parola, P., Paddock, C. D., Socolovschi, C., Labruna, M. B., Mediannikov, O., Kernif, T., . . . Raoult, D. (2013). Update on tick-borne rickettsioses around the world: a geographic approach. Clin Microbiol Rev, 26(4), 657-702. doi:10.1128/CMR.00032-13

26/4/657 [pii]

Rosenblum, M. J., Masland, R. L., & Harrell, G. T. (1952). Residual effects of rickettsial disease on the central nervous system; results of neurologic examinations and electroencephalograms following Rocky Mountain spotted fever. AMA Arch Intern Med, 90(4), 444-455. doi:10.1001/archinte.1952.00240100021003

Sanchez, J. L., Candler, W. H., Fishbein, D. B., Greene, C. R., Cote, T. R., Kelly, D. J., . . . Johnson, B. J. (1992). A cluster of tick-borne infections: association with military training and asymptomatic infections due to Rickettsia rickettsii. Trans R Soc Trop Med Hyg, 86(3), 321-325. doi:10.1016/0035-9203(92)90330-f

Shapiro, M. R., Fritz, C. L., Tait, K., Paddock, C. D., Nicholson, W. L., Abramowicz, K. F., . . . Eremeeva, M. E. (2010). Rickettsia 364D: a newly recognized cause of eschar-associated illness in California. Clin Infect Dis, 50(4), 541-548. doi:10.1086/649926

Straily, A., Stuck, S., Singleton, J., Brennan, S., Marcum, S., Condit, M., . . . Paddock, C. D. (2019). Antibody titers reactive with Rickettsia rickettsii in blood donors and implications for surveillance of spotted fever rickettsiosis in the United States. J Infect Dis. doi:10.1093/infdis/jiz316

Varela-Stokes, A. S., Paddock, C. D., Engber, B., & Toliver, M. (2011). Rickettsia parkeri in Amblyomma maculatum ticks, North Carolina, USA, 2009-2010. Emerg Infect Dis, 17(12), 2350-2353. doi:10.3201/eid1712.110789

Walker, D. H., Paddock, C. D., & Dumler, J. S. (2008). Emerging and re-emerging tick-transmitted rickettsial and ehrlichial infections. Med Clin North Am, 92(6), 1345-1361, x. doi:10.1016/j.mcna.2008.06.002

Wikswo, M. E., Hu, R., Dasch, G. A., Krueger, L., Arugay, A., Jones, K., . . . Eremeeva, M. E. (2008). Detection and identification of spotted fever group rickettsiae in Dermacentor species from southern California. J Med Entomol, 45(3), 509-516. doi:10.1603/0022-2585(2008)45[509:daiosf]2.0.co;2

Yevich, S. J., Sanchez, J. L., DeFraites, R. F., Rives, C. C., Dawson, J. E., Uhaa, I. J., . . . Fishbein, D. B. (1995). Seroepidemiology of infections due to spotted fever group rickettsiae and Ehrlichia species in military personnel exposed in areas of the United States where such infections are endemic. J Infect Dis, 171(5), 1266-1273. doi:10.1093/infdis/171.5.1266

Yoshimizu, M. H., & Billeter, S. A. (2018). Suspected and confirmed vector-borne Rickettsioses of North America associated with human diseases. Trop Med Infect Dis, 3(1), doi:10.3390/tropicalmed3010002.

Zientek, J., Dahlgren, F. S., McQuiston, J. H., & Regan, J. (2014). Self-reported treatment practices by healthcare providers could lead to death from Rocky Mountain spotted fever. J Pediatr, 164(2), 416-418. doi:10.1016/j.jpeds.2013.10.008