# Presentation: 161248

## Rocky Mountain spotted fever:  From dog ticks to doxycycline 

***David L. Swerdlow, MD***
***Rickettsial Zoonoses Branch ***
***Division of Viral and Rickettsial Diseases ***
***National Center for Zoonotic, Vectorborne and Enteric Diseases***

## Tick-borne infectious diseases in the United States

- Lyme disease
- Ehrlichioses
- Rocky Mountain spotted fever
- Babesioses
- Colorado tick fever
- Tularemia
- Tick-borne relapsing fever

## RMSF: background

- The most severe rickettsial illness of humans, caused by *Rickettsia rickettsii*
- First specific notation of the disease in 1896
- Endemic to the Americas
- Until recently, 300-800 U.S. cases/year

## Rocky Mountain spotted fever: why is it important?

- Widely distributed with significant morbidity and mortality
- Difficult to diagnose
- Rapid diagnosis and treatment prevents deaths

## General properties

**Small, coccobacillary bacteria**
**Slow growing**
**Intracellular**

## Gimenez staining for R. rickettsii

## BACKGROUND:The Primary Tick Vectors of RMSF

**Notes:**
The primary vectors for RMSF in the US are Dermacentor variabilis the American dog tick, widely distributed east of the Rocky Mountains and Dermacentor andersoni,  the Rocky mountain wood tick which is found in the Rocky Mountain states.

## RMSF Incidence by County, 1997-2002

**Notes:**
RMSF is endemic in the US. About 700-1000 cases are reported from the US each year, occurring mostly in the southeast and southcentral US

## RMSF: epidemiology and patient demographics

- Over 90% of cases occur during April-September
- Peridomestic acquisition may account for majority of cases
- Age-specific incidence highest in children, disease more frequent in males
- Case clusters occur in hyperendemic foci

## RMSF: clinical manifestations

- Early: high fever, severe headache, myalgia, and gastrointestinal symptoms
- Late: rash, photophobia, confusion, ataxia, seizures, cough, dyspnea, arrhythmias, jaundice, severe abdominal pain
- Thrombocytopenia, hyponatremia
- Long term sequelae: CNS deficits, amputations

## RMSF: the rash

- Generally not apparent until 2-5 days after onset
-    of fever
- Begins as 1 to 5 mm macules, typically on ankles, wrists, and forearms, spreads centripetally to trunk
- Petechial rash occurs on or after day 6
- Rash may be asymmetric, localized, or absent

## Slide 12

## Slide 13

## Severe sequelae

## RMSF: frequent initial diagnoses

- 1. Viral illness
- 2. Fever of undetermined etiology
- 3. Bacterial sepsis
- 4. Upper or lower respiratory tract infections,
-      acute appendicitis, cholecystitis *	*

## Differential Diagnosis of Rocky Mountain Spotted Fever

| Disease | Season | History/ Onset | Rash | Other Features |
| --- | --- | --- | --- | --- |
| Rocky Mountain Spotted fever | Late spring/
summer | Exposure to ticks, travel to endemic areas; starts with fever and develops rash after 2 to 3 days | Starts peripherally and spreads centrally; most marked on extremities, usually involves the palms and soles. | Often associated with thrombocytopenia and hyponatremia |
| Meningococcal infections | Late winter/ early spring | Often epidemics: fever and rash usually appear within 24 hours | Two patterns: macular and petechial lesions, few in number and generalized in distribution. | Gram-negative dipllococci in petechiae, buffy coat or in the CSF |
| Enteroviral Infections | Summer-fall | Febrile, illness in family or community, fever and rash often appear together | Starts on face or trunk, may involve palms and soles. | May be associated with aseptic meningitis |
| Measles | Winter-spring | Exposure to measles or killed measles vaccine, severe prodrome | Starts on head and spreads to trunk and extremities | Koplik spots during prodrome |

**Differential Diagnosis of Rocky Mountain Spotted Fever**

## Confirmation of R. rickettsii 

**Notes:**
We identified cases through active surveillance at regional hospitals. 

Environmental assessments were then conducte. Engorged ticks were collected from patient dogs, and flat ticks were collected from patient homes.

Our goal was to test large numbers of flat, 
non-engorged ticks, to demonstrate the presence of R. rickettsii in the ticks
 without the possibility of the rickettsia having been acquired from a recent blood meal
Patient specimens were collected for diagnostic confirmation of R. rickettsii at cdc.
Indirect Immunofluorescence assay , Immunohistochemical staining, 
PCR, and Culture isolation were applie.

## Serologic diagnosis of RMSF

**85% of patients lack diagnostic titers in the first week of illness**
**As many as 50% of patients lack a diagnostic titer 7-9 days after onset of illness**
**Need to test acute and convalescent samples (2-4 weeks apart)**
**Indirect immunofluorescence assay (IFA)-  four fold rise in titers confirmatory**
**ELISA not quantitative so can’t quantify increases between acute and convalescent samples**

## Deaths attributable to RMSF

- Case-fatality ratio as high as 20%-30% in untreated patients
- CFR highest in older adults and males
- Disease kills otherwise healthy adults and children
- Clinical progression may be rapid (median time to death 8 days)

## RMSF deaths in the United States,

** ****1940-1997**

- 1940

- 1950

- 1960

- 1970

- 1980

- 1990

- 10

- 50

- 100

- 140

## RMSF treatment

- Tetracyclines the drugs of choice: clinical response within 24-72 h
- Chloramphenicol an alternative therapy for some patients with RMSF
- Other broad-spectrum antimicrobials characteristically ineffective

## Antimicrobial therapy of RMSF 

- Pregnant adult or
- tetracycline allergic

- Non-pregnant adult
- or child _>_45 kg

- Child <45 kg

- Chloramphenicol
- 500 mg qid i.v.

- Doxycycline
- 100 mg bid
- p.o. or i.v.

- Doxycycline
- 4.4 mg/kg/day
- in 2 divided
- doses p.o. or i.v.

-  Therapy should be continued at least 72 h after defervescence
-  AND until evidence of clinical improvement

## RMSF prevention

- Disease awareness and recognition
- Use of protective clothing and repellents
- Avoid tick areas
- Antimicrobial prophylaxis  following tick bite not recommended
- Careful inspection for ticks and prompt removal (“grace period”)

## Prevention and Control

**Prevention and Control**

-  **Wear light-colored clothing**
** ****Tuck your pants legs into  **
**  ****your socks**
** ****Use masking tape on your**
**  ****upper leg-sticky side up**
** ****Apply repellant to**
**  ****discourage tick attachment**

## Prevention and Control (cont.)

**Tick check and removal**
**Transmission unlikely to occur in less than 6 hours**
**Use fine-tipped tweezers**

## Surveillance and reporting

- RMSF is a nationally reportable disease
- Cases should be reported to state Health Department
- Reports then submitted to CDC

## RMSF Cases and Incidence

## Top Reporting States: Cases

## Human Ehrlichiosis Cases

## Spread of Ehrlichiosis Cases, WI

- 2002

- 2005

## Spread of Ehrlichiosis Cases, MN

- 2002

- 2005

## Lyme Disease

## Explanations for Increases

## Summary

- RMSF is a potentially life-threatening disease, endemic throughout much of the United States
- Broad differential diagnoses, early disease difficult to diagnose even for experienced physicians
- Confirmatory assays:
- 	Serology
- 	Polymerase chain reaction
- 	Immunopathology
- 	Isolation
- Consider RMSF as a cause of unexplained fever in spring and summer
- Doxycycline the drug of choice, regardless of age

## RMSF in eastern Arizona

**Since 2002, 24 cases RMSF mostly children with 2 deaths in a small community**
**Incidence rate 300 times higher than expected **

**Notes:**
additional cases of RMSF were reported Beginning in May of 2004, from the same community as the previous cases. 
We then initiated an EpiAid with the following objectives:
To Determine magnitude of the outbreak and to collect ticks from the environment and assess for the presence of R. rickettsii. We also wanted to link our epidemiologic findings with laboratory evidence for transmission of r. rickettsii by rhipicephalus sanguineus ticks. 
Because of previous observations in 2003, the big question to us was, Is Rh. sanguineus the vector of R. rickettsii in this outbreak?

## Summary of investigationRh. sanguineus vector of RMSF

***Dermacentor *****ticks not found**
**High density of *****Rh. sanguineus *****ticks surrounding patient homes and on dogs**
***Rh. sanguineus *****ticks found attached to patient**
**Confirmed the presence of *****R. rickettsii***** in ticks by PCR, sequencing/RFLP, culture**
***First reported evidence of RMSF associated with Rhipicephalus sanguineus in the United States***

**Notes:**
In conclusion, Our investigation showed that Rh. sanguineus appears to be the vector causing the RMSF outbreak 
We found a High prevalence of Rh. ticks surrounding case homes and on dogs, we found  Rh. sanguineus ticks found attached to case-patients, and we found no Dermacentor Ticks despite an extensive search 
Our Laboratory evidence was crucial to link the  high densities of Rh. sanguineus in peridomestic settings with Rickettsia rickettsii
This ourbreak was the first reported evidence of RMSF associated with Rh. sanguineus in the United States

## Rhipicephalus sanguineus

***Rhipicephalus sanguineus***
**(Brown dog tick)**

**Notes:**
These pictures showa known vector of R. rickettsii, Dermacentor variabilis on the left, compared to the tick we found in large numbers, rhipicephalus sanguineus on the right, a previously unrecognized vector of RMSF in the US.

## Environmental Assessment

**Typical peridomestic environment surrounding case-patient homes, found to be heavily populated by *****Rh. sanguineus***** ticks**

**Environmental Assessment**

**Notes:**

Ticks were collected from the peridomestic environment surrounding case homes. These pictures demonstrate the microhabitats found to be heavily populated by Rh sanguineus ticks: discarded furniture, dogs, and surrounding vegetation.

## Community and physician education
Treatment of homes
Treatment of dogs 
Animal control

**Treatment of homes**
**Treatment of dogs **
**Animal control**

**Collaborative Intervention**

**Notes:**
Recognizing the need for an immediate intervention, we Created an RMSF Task Force consisting of the Indian Health Service, Tribal members/programs, Arizona Dept Health Services, and CDC
Our ongoing interventions include community and physician education, treatment of homes with pesticides, treatment of dogs with tick preventives, and environmental clean-up of tick habitats

## Get Rid of Ticks on Dogs

## Keep Ticks Off Children

## Slide 42

**Notes:**
Our investigation resulted in many targeted educational programs to 
Encourage early recognition of RMSF and exclustion of brown dog ticks
from the environment. These ongoing efforts have been very well received 

## Acknowledgments

- Christopher Paddock, MD
- John Openshaw
- Jennifer McQuiston, DVM