Expanding Recognition of Rickettsia parkeri Rickettsiosis in Southern Arizona,2016

Abstract

Rickettsia parkeri rickettsiosis is an emerging, tick-borne disease in the United States (US), transmitted by the bite of Amblyomma maculatum group ticks. Clinical manifestations include fever, headache, myalgia, maculopapular rash, and a characteristic eschar that forms at the site of the tick bite. Arizona's index case of R. parkeri rickettsiosis was reported in 2014. Seven additional confirmed and probable cases were identified during 2016–2017 through routine investigation of electronic laboratory reports and by self-reporting to public health authorities. Serum samples were evaluated for immunoglobulin G antibodies reactive with antigens of Rickettsia rickettsii (the agent of Rocky Mountain spotted fever [RMSF]) and R. parkeri using indirect immunofluorescence antibody tests. Eschar swab specimens were evaluated using Rickettsia genus-specific and R. parkeri-specific real-time PCR assays. Patients (six male, one female) ranged in age from 29 to 69 years (median of 41 years), and became ill between July 2016 and September 2017. Fever (6/7), myalgia (5/7), and arthralgia (5/7) were most commonly reported and 5/7 patients had a documented eschar. All patients reported a tick bite acquired in southern Arizona within 2–8 days before illness onset. Four patients worked as U.S. Border Patrol agents. Antibodies reactive to R. rickettsii, R. parkeri, or to both antigens were detected in all patients. Seroconversions between acute and convalescent-phase samples were identified for two patients and DNA of R. parkeri was identified in eschar swab samples from two patients. R. parkeri rickettsiosis is endemic to a region of the southwestern United States and presents an occupational risk that could be lessened by prevention messaging to Border Patrol agents. RMSF, a closely related and more severe spotted fever rickettsiosis, is also endemic to Arizona. Public health agencies can assist clinicians in distinguishing these two infections clinically through education and accessing species-specific diagnostic assays that can improve surveillance efforts for both diseases.

Introduction

R ickettsia parkeri is one of several species of pathogenic spotted fever group rickettsiae (SFGR) distributed throughout the Western hemisphere. The bacterium is transmitted predominantly by ticks of the Amblyomma maculatum group (Paddock et al. 2004). The clinical manifestations of R. parkeri rickettsiosis most often include an inoculation eschar at the tick bite site, followed by fever and some combination of other features that headache, fatigue, myalgia, and a sparse maculopapular or papulovesicular rash. R. parkeri rickettsiosis can present as a self-limiting illness and its signs and symptoms can resolve effectively with doxycycline (Paddock et al. 2004, Biggs et al. 2016).

The first confirmed case of R. parkeri rickettsiosis was described in 2004 (Paddock et al. 2004) and since that report, there have been ∼40 cases from nine states in the southeastern and mid-Atlantic United States (Paddock and Goddard 2015, Kelman et al. 2018). During 2014 and 2015, two cases of R. parkeri rickettsiosis were identified in southern Arizona and associated with bites from ticks identified morphologically as Amblyomma triste, a member of the A. maculatum group (Herrick et al. 2016). Subsequent environmental surveillance in southern Arizona identified A. maculatum group ticks in three counties at or near the U.S.-Mexico border. R. parkeri was detected in 24% of the total specimens collected from this region (Allerdice et al. 2017).

Increased awareness of the pathogen and vector tick species in southern Arizona has facilitated the recognition of additional cases of R. parkeri rickettsiosis. Herein, we describe the clinical and epidemiological characteristics of seven autochthonous cases of this disease, identified from southern Arizona during 2016–2017.

Materials and Methods

Identification of case patients

Spotted fever rickettsioses, including Rocky Mountain spotted fever (RMSF) and R. parkeri rickettsiosis, are nationally notifiable conditions and reportable to public health authorities by health care providers and clinical laboratories in Arizona. Four cases were identified through routine review of electronic laboratory reports; three cases were self-reported to county and state public health personnel. Epidemiological and clinical data were collected using a standardized case report form.

Diagnostic testing

For most patients, serum, whole blood, or eschar swab specimens were submitted to the Centers for Disease Control and Prevention (CDC) for diagnostic evaluation. Serum samples were tested for immunoglobulin G (IgG) antibodies reactive with antigens of R. rickettsii and R. parkeri by using an indirect immunofluorescence antibody (IFA) technique. Samples were screened at an initial dilution of 1/32 and diluted serially to endpoint. A fluorescein isothiocyanate-labeled goat anti-human conjugate, reactive with heavy chains (gamma) of IgG (Kirkegaard & Perry Laboratories, Inc., Gaithersburg, MD), was used at 1/150. Titers were expressed as the reciprocal of the last dilution exhibiting specific fluorescence. Specimens with IgG antibody titers ≥64 were considered positive.

DNA was extracted from eschar swab specimens by using a QIAamp DNA Mini Kit (Qiagen, Valencia, CA) and eluted in a final volume of 200 μL. Five μL of extracted DNA was screened using a real-time PCR assay targeting a segment of the 23S rRNA gene of all known Rickettsia species (Kato et al. 2013). Threshold cycle values <40 were considered positive. Positive samples were subsequently tested using separate, real-time PCR assays for R. rickettsii and R. parkeri, as described previously (Jiang et al. 2012, Kato et al. 2013).

A confirmed case of R. parkeri rickettsiosis was defined as a clinically compatible illness with serologic evidence of a fourfold rise in IgG antibodies reactive with SFGR antigens, or PCR amplification of DNA of R. parkeri from a clinical specimen. A probable case was defined as a clinically compatible illness with serologic evidence of IgG antibodies reactive with antigens of SFGR at a titer of ≥64.

Results

Clinical presentations

Three confirmed and four probable cases, comprising six male and one female patient from 29 to 69 years of age (median of 41 years), were identified during 2016–2017 (Table 1). Disease onset occurred during July 2016 through September 2017 and in most patients (86%) was characterized by fever (temperature ≥38.5°C), with accompanying myalgia (71%), arthralgia (71%), and/or an eschar (71%) (Table 2). Of the probable patients, three described an eschar. Figure 1 illustrates the early and left stage eschar from patient 7. Among all seven patients, rash was reported for only three and was described as a diffuse exanthem involving the arms, neck, and chest (patient 2), sparse maculopapular rash (patient 4), and diffuse nonpruritic, nonblanching raised maculopapular rash on the extremities and trunk (patient 5). One case (patient 2) with history of an inflammatory arthritic disease was hospitalized for 4 days. All patients reported a tick bite acquired in southern Arizona within 2–8 days before illness onset. Three patients (two confirmed and one probable) described the ticks as dark brown or black with white or yellowish markings, which is similar to the ornamentation of Amblyomma spp. ticks. Six of the seven patients received doxycycline within 1–15 days of illness onset and recovered completely from their illnesses.

FIG. 1.

Early (left) and late- (right) stage eschar at the base of neck of patient 7, occurring at the site of tick bite sustained while working in the Whetstone Mountains of Arizona.

Table 1.

Epidemiological, Clinical, and Laboratory Characteristics of Patients with Rickettsia parkeri Rickettsiosis Identified in Southern Arizona, 2016–2017

Patient	Age	Sex	Month/year of onset	Exposure location (county)	Clinical symptoms	Immunoglobulin G antibody titer(s) reactive with R. rickettsii or R. parkeri	PCR
1	62	M	September 2016	Cienega Creek (Pima)	Fever (37.9°C), chills, fatigue, myalgia, arthralgia	1024, 8192 (Rr); 2048, 8192 (Rp)	ND
2	41	M	August 2016	Huachuca Mountains (Cochise)	Fever (38.9°C), headache, photophobia, myalgia, arthralgia, macular rash, eschar	64 (Rr); 256 (Rp)	ND
3	66	M	September 2016	Pearce (Cochise)	Fever, chills, dizziness, weakness, malaise, arthralgia	512 (Rr); 1024 (Rp)	ND
4^a	38	M	July 2016	Patagonia Mountains (Santa Cruz)	Fever (38.3°C), headache, myalgia, arthralgia, rash, eschar	256 (Rr)^b	ND
5^a	69	F	August 2017	Chiricahua Mountains (Cochise)	Fever (38.9°C), headache, severe fatigue, myalgia, arthralgia, rash, eschar	256, 128 (Rr); 512, 1024 (Rp)	Positive
6	37	M	August 2017	Patagonia Lake (Santa Cruz)	Fatigue, chills, headache, malaise, eschar	32 (Rr); 64 (Rp)	Positive
7	29	M	September 2017	Whetstone Mountains (Cochise)	Fever (39.5°C), chills, arthralgia, eschar (Fig. 1)	128 (Rr); 512 (Rp)	Negative

Detailed case reports included for these patients.

Sample not available for R. parkeri immunofluorescence antibody testing.

ND, not done; Rp, R. parkeri; Rr, R. rickettsii.

Table 2.

Demographic and Clinical Characteristics of Patients with R. parkeri Rickettsiosis from Southern Arizona, 2016–2017, and Comparison with Features of 27 Other Patients Reported from Case Series in the United States, 1998–2014

	This study (n = 7)	Paddock et al., 2008 (n = 12)	Cragun et al., 2010 (n = 3)	Ekenna et al., 2014 (n = 5)	Straily et al., 2016 (n = 5)	Kelman et al., 2018 (n = 3)
Characteristic
States(s) of exposure	AZ	AL, FL, KY, MD, MS, SC, VA	SC, TX	MS	GA	VA
Period of series	2016–2017	1998–2007	2008–2009	2007–2012	2012–2014	NR
No. (%) male	6 (86)	8 (67)	3 (100)	3 (60)	5 (100)	3 (100)
Age range (years)	29–69	23–78	38–62	45–72	27–72	46–60
No. (%) with fever	6 (86)	12 (100)	3 (100)	5 (100)	2 (40)	2 (67)
No. (%) with headache	5 (71)	10 (83)	2 (67)	5 (100)	2 (40)	2 (67)
No. (%) with eschar	5 (71)	11 (92)	3 (100)	4 (80)	5 (100)	3 (100)
No. (%) with rash	3 (42)	10 (83)	3 (100)	5 (100)	1 (20)	2 (67)
No. (%) with fatigue or malaise	5 (71)	NR	3 (100)	2 (40)	2 (40)	2 (67)
No. (%) with myalgia	5 (71)	11 (92)	1 (33)	4 (80)	3 (60)	3 (100)
No. (%) with arthralgia	5 (71)	9 (75)	1 (33)	3 (60)	2 (40)	NR
No. (%) with nausea	1 (14)	1 (8)	NR	1 (17)	NR	1 (33)

NR, not reported.

IgG antibodies reactive with R. rickettsii, R. parkeri, or both antigens were detected in serum specimens of all patients, and titers to R. parkeri were fourfold greater for one patient who had both antigens used in the IFA assay (Table 1). Seroconversions to one or both antigens were identified for patients for whom acute and convalescent-phase samples were collected. Eschar swabs were collected from three patients 6–13 days after illness onset. Two of these (collected on days 8 and 13) were positive by the Rickettsia genus-specific, real-time PCR assay. Additional analysis by real-time PCR assays revealed positive results for R. parkeri and negative results for R. rickettsii for both samples. Reports for two patients (cases 4 and 5) with unusual clinical courses are described in greater detail.

Report 1

A 38-year-old border patrol agent was evaluated at an emergency room in early August 2017 with complaints of dizziness and lower extremity arthralgia for 2 days. He reported a tick bite to the back of his neck 6 days earlier while working in the Santa Rita Mountains. The patient was afebrile and no eschar was noted at the bite site. He was prescribed doxycycline (100 mg twice daily by mouth) for 10 days. A serum sample was obtained 2 days after symptoms onset and demonstrated IgG antibodies reactive with R. rickettsii at a titer of 256.

While interviewing the agent, local public health authorities learned that he had experienced a clinically similar, but more severe illness the previous summer, (2016) while working in the Patagonia Mountains. During that episode, he noticed a red, swollen, and tender lesion on the back of his neck 6 days after a tick bite at that location, followed by fever (38.3°C), headache, arthralgia, and rash. He presented to a local health care facility where the medical staff noted a raised, indurated, and erythematous lesion on his neck measuring 1.2 cm in greatest dimension. He was prescribed amoxicillin/clavulanic acid and discharged home. Five days after discharge, the medication was changed to trimethoprim/sulfamethoxazole for a suspected allergic reaction. Because of continued fever, headache, and arthralgia the agent presented to a second health care facility 9 days after initially seeking care. The swelling and rash had resolved; however, a dark, 1-cm scab was identified on the back of his neck. He was started on doxycycline and his symptoms quickly resolved. A serum sample collected 36 days after illness (2016) onset tested positive for IgG antibodies reactive with R. rickettsii at a titer of 256 when evaluated by IFA at a commercial laboratory.

Report 2

A 69-year-old woman sustained a tick bite on her right breast while hiking along Cave Creek Canyon in the Chiricahua Mountains during late July 2017. Approximately 10 days later, she subsequently developed severe fatigure, and a generalized, nonpruritic, erythematous rash on her arms, legs, chest, back, and face. Nine days after illness onset, she was evaluated at a health care facility and prescribed clindamycin for suspected wound infection and cellulitis. The patient also contacted local and state public health authorities after learning that A. maculatum group ticks were present in the Chiricahua Mountains and that the ticks were found to transmit a recently identified pathogen. Because her symptoms did not improve, she returned to her physician 3 days later. At that time, a 2-cm eschar was noted at the site of the tick bite, along with a diffuse, nonpruritic, nonblanching, maculopapular rash. The patient was severely allergic to doxycycline, therefore public health authorities recommended to her clinician treatment with rifampin (450 mg by mouth twice a day) for 10 days. The patient responded well to the ripampin regimen and reported full resolution of fatigue and myalgia after several weeks. Serum specimens obtained at 12 and 54 days after symptom onset revealed IgG antibodies reactive with R. parkeri antigens at titers of 512 and 1024, respectively. Serum samples were also reactive to R. rickettsii with IgG antibody titers at 256 and 128, respectively. Molecular evaluation of an eschar swab sample collected ∼3 weeks after symptom onset revealed R. parkeri DNA.

Discussion

This series provides further evidence that R. parkeri rickettsiosis represents a tick-borne disease of public health concern in southern Arizona. Since 2014, a total of nine persons have been diagnosed with this infection following exposures to A. maculatum group ticks in Santa Cruz, Pima, and Cochise counties (Herrick et al. 2016; data herein). The clinical characteristics reported in this series resemble those identified in patients from other regions of the United States (Table 2) with respect to the frequent constellation of eschar, fever, headache, and myalgia (Whitman et al. 2007, Paddock et al. 2008, Cragun et al. 2010, Ekenna et al. 2014, Straily et al. 2016). Similar to most other series, rash was variable and identified in fewer than half of the patients. Despite the presence of an eschar, five cases had a delayed diagnosis or misdiagnosis, suggesting a lack of clinician awareness. Cases presented in this series were predominantly male, including four Border Patrol agents who acquired the infection during occupational activities in mountainous areas inhabited by A. maculatum group ticks. All patients in this series were infected during July through September, corresponding to monsoon season in the southwestern United States, and the period when adult stage ticks of this species are most abundant in this region (Mertins et al. 2010, Allerdice et al. 2017, Lado et al. 2018).

Of particular interest is the apparent reexposure of a patient to R. parkeri approximately 1 year after his primary infection that resulted in a milder, nonfebrile infection. A similar occurrence was described previously (Herrick et al. 2016). Finally, one patient with doxycycline intolerance was treated successfully with rifampin. Although doxycycline is the antibiotic of choice for treating spotted fever rickettsioses in patients of all ages, some Rickettsia species (including R. parkeri) are susceptible to rifampin (Rolain et al. 1998), and limited data suggest that this antibiotic could be an alternate therapy in specialized situations such as non-life-threatening, PCR-confirmed infections with rifampin-susceptible rickettsial pathogens (Strand et al. 2017).

RMSF, caused by R. rickettsii, is also endemic in many regions of Arizona, although almost all cases occur on American Indian reservations (Demma et al. 2005). RMSF and R. parkeri rickettsiosis share several clinical features such as fever, headache, malaise, and rash (Paddock et al. 2008, Biggs et al. 2016); nonetheless, RMSF is far more severe and can cause irreversible and life-threatening vascular damage if treatment is delayed or not administered within the first 5 days of illness. The hallmark rash of RMSF usually appears as small, flat, nonpruritic macules on the wrists, forearms, and ankles, then spreads centrally, eventually becoming a generalized petechial exanthema (Biggs et al. 2016). Unlike R. parkeri rickettsiosis, an eschar is only rarely described in patients with RMSF (Paddock et al. 2008). The case fatality rate of RMSF in Arizona is ∼6% (ADHS unpublished data). By comparison R. parkeri rickettsiosis is a much less severe infection, with low rates of hospitalization and no reported deaths (Paddock et al. 2008).

The epidemiologic and ecologic characteristics of these infections also differ. In Arizona, R. rickettsii is transmitted by Rhipicephalus sanguineus sensu lato (the brown dog tick), and infections are acquired predominantly in peridomestic environments in communities with large numbers of free-roaming dogs. Cases are often clustered within communities, and the highest age-associated rates of disease occur among persons ≤19 years of age, presumably due to increased exposures to dogs around their homes (Demma et al. 2005). By comparison, cases of R. parkeri rickettsiosis are acquired in relatively remote and isolated riparian habitats, occur sporadically, and predominantly among adults working or recreating in these regions.

The most common laboratory test used to support a diagnosis of RMSF or R. parkeri rickettsiosis is antibody detection by the IFA method; nonetheless, antigens of all SFGR are cross-reactive and antibodies elicited by R. parkeri often react with antigens of R. rickettsii, as seen with patients from this series. Molecular methods that amplify specifically DNA of R. parkeri are used increasingly to confirm cases of R. parkeri rickettsiosis, and eschar swabs in particular provide a simple, relatively noninvasive, and sensitive method to collect samples for subsequent PCR analysis (Myers et al. 2013). Clinicians are encouraged to coordinate all sample submissions with their local or state public health agencies.

The prevalence of R. parkeri rickettsiosis in southern Arizona is presently unknown. Increased awareness of the disease and best-practice diagnostic approaches could improve clinical recognition and surveillance. Staff from the Arizona Department of Health Services and CDC conducted a series of educational sessions with groups at several regional border patrol stations and health care facilities during 2016, which likely improved awareness among persons at greatest risk, as well as health care providers in the region, leading to the recognition of some of the patients described in this series. Comprehensive clinical and epidemiological education can enhance health care and public health understanding of this emerging tick-borne disease.

Conclusions

RMSF and R. parkeri rickettsiosis are nationally notifiable spotted fever rickettsioses. Given the clinical similarities and limited clinician awareness, cases of R. parkeri rickettsiosis are potentially misdiagnosed as RMSF. Additionally, there is no known commercially available serologic assay that can distinguish between these species; specific testing for R. parkeri can be conducted at reference laboratories. Accurate diagnosis is best accomplished using molecular methods (i.e., PCR of an eschar biopsy). Both of these rickettsial infections respond to doxycycline and treatment should not be withheld until diagnostic confirmation. RMSF has been well-documented across Arizona American Indian reservations and is the predominant tick-borne disease in the state. The expanding recognition of R. parkeri rickettsiosis as a recreational and an occupational risk in southern Arizona demonstrates a need for continued surveillance. Clinical education by public health agencies can help clinicians and the public identify and treat these diseases and improve surveillance by directing diagnostic endeavors that distinguish between infections caused by R. parkeri and R. rickettsii.

Footnotes

Acknowledgments

The authors wish to thank Naomi Drexler, Elizabeth Lueck, Michele Lanan, and the U.S. Border Patrol Service for their partnership. We also thank staff from the Arizona State Public Health Laboratory, Arizona Department of Health Services, and CDC Rickettsial Zoonoses Branch and Diagnostic Laboratory for their assistance and support.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

This work was supported by the CDC Epidemiology and Laboratory Capacity (ELC; grant no. CK14-401) for Infectious Diseases cooperative agreement.

References

Allerdice

, Beati

, Yaglom

, Lash

, et al. Rickettsia parkeri (Rickettsiales: Rickettsiaceae) detected in ticks of the Amblyomma maculatum (Acari: Ixodidae) group collected from multiple locations in southern Arizona. J Med Entomol, 2017; 54:1743–1749.

Biggs

, Barton-Behravesh

, Bradley

, Dahlgren

, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis—United States. MMWR, 2016; 65:1–44.

Cragun

, Bartlett

, Ellis

, Hoover

, et al. The expanding spectrum of eschar-associated rickettsiosis in the United States. Arch Dermatol, 2010; 126:641–648.

Demma

, Traeger

, Nicholson

, Paddock

, et al. Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med, 2005; 353:587–594.

Ekenna

, Paddock

, Goddard

. Gulf Coast tick rash illness in Mississippi caused by Rickettsia parkeri . J Mississippi Med Assoc, 2014; 216–219.

Herrick

, Pena

, Yaglom

, Layton

, et al. Rickettsia parkeri rickettsiosis, Arizona, USA. Emerg Infec Dis, 2016; 22:780–785.

Jiang

, Stromdahl

, Richards

. Detection of Rickettsia parkeri and Candidatus Rickettsia andeanae in Amblyomma maculatum Gulf Coast ticks collected from humans in the United States. Vector Borne Zoonotic Dis, 2012; 12:175–182.

Kato

, Chung

, Robinson

, Austin

, et al. Assessment of real-time PCR assay for detection of Rickettsia spp. and Rickettsia rickettsii in banked clinical samples. J Clin Microbiol, 2013; 51:314–317.

Kelman

, Thompson

, Hynes

, Bergman

, et al. Rickettsia parkeri infections diagnosed by eschar biopsy, Virginia, USA. Infect, 2018; 46:559–563.

10.

Lado

, Nava

, Mendoza Uribe

, et al. The Amblyomma maculatum Koch, 1844 (Acari: Ixodidae) group of ticks: Phenotypic plasticity or incipient speciation?. Parasite Vector, 2018; 11:610.

11.

Mertins

, Moorhouse

, Alfred

, Hutchinson

. Amblyomma triste (Acari: Ixodidae): North American collection records, including the first from the United States. J Med Entomol, 2010; 47:536–542.

12.

Myers

, Lalani

, Dent

, Jiang

, et al. Detecting Rickettsia parkeri infections from eschar swab specimens. Emerg Infec Dis, 2013; 19:778–780.

13.

Paddock

, Sumner

, Comer

, Zaki

, et al. Rickettsia parkeri: A newly recognized cause of spotted fever rickettsiosis in the United States. Clin Infec Dis, 2004; 38:805–811.

14.

Paddock

, Finley

, Wright

, Robinson

, et al. Rickettsia parkeri rickettsiosis and its clinical distinction from Rocky Mountain spotted fever. Clin Infec Dis, 2008; 47:1188–1196.

15.

Paddock

, Goddard

. The evolving medical and veterinary importance of the Gulf Coast tick (Acari: Ixodidae). J Med Entomol, 2015; 52:230–252.

16.

Rolain

, Maurin

, Vestris

, Raoult

. In vitro susceptibilities of 27 rickettsiae to 13 antimicrobials. Antimicrob Agents Chemother, 1998; 42:1537–1541.

17.

Straily

, Feldpausch

, Ulbrich

, Schell

, et al. Rickettsia parkeri rickettsiosis—Georgia, 2012–2014. MMWR, 2016; 65:718–719.

18.

Strand

, Paddock

, Rinehart

, et al. African tick bite fever treated successfully in a patient with doxycycline intolerance. Clin Infect Dis, 2017; 65:1582–1584.

19.

Whitman

, Richards

, Paddock

, Tamminga

, et al. Rickettsia parkeri infection after tick bite, Virginia. Emerg Infec Dis, 2007; 334–336.

Expanding Recognition of Rickettsia parkeri Rickettsiosis in Southern Arizona,2016–2017

Abstract

Introduction

Materials and Methods

Identification of case patients

Diagnostic testing

Results

Clinical presentations

Report 1

Report 2

Discussion

Conclusions

Footnotes

Acknowledgments

Author Disclosure Statement

Funding Information

References