What are rickettsial illnesses?

Rickettsial Illnesses: Comprehensive Overview

Definition and Classification

Rickettsial diseases are life-threatening bacterial infections caused by obligate intracellular organisms in the order Rickettsiales, transmitted primarily by arthropod vectors including ticks, fleas, lice, and mites. 1

Major Categories in the United States

Tickborne Rickettsial Diseases:

• Rocky Mountain Spotted Fever (RMSF) - caused by Rickettsia rickettsii, the most severe rickettsial illness in the United States 1
• Other Spotted Fever Group (SFG) Rickettsioses - caused by Rickettsia parkeri and Rickettsia species 364D 1
• Ehrlichiosis - including human monocytic ehrlichiosis (Ehrlichia chaffeensis), Ehrlichia ewingii infection, and Ehrlichia muris-like (EML) agent infection 1
• Anaplasmosis - caused by Anaplasma phagocytophilum (human granulocytic anaplasmosis) 1

Non-Tickborne Rickettsial Diseases (not detailed in US guidelines but mentioned):

• Flea-borne typhus (Rickettsia typhi) 1
• Louse-borne typhus (Rickettsia prowazekii) 1
• Mite-borne rickettsialpox (Rickettsia akari) 1
• Scrub typhus (Orientia tsutsugamushi) - significant in South Asia, Southeast Asia, and Western Pacific 2

Microbiology and Pathophysiology

Rickettsiae are small, obligately intracellular, gram-negative coccobacilli that multiply within endothelial cells, causing vasculitis responsible for clinical manifestations. 3, 4

• These organisms are maintained in nature through cycles involving mammalian reservoirs and arthropod vectors, with humans as incidental hosts 1
• They are primarily bacteriostatic and exert antimicrobial effects through protein synthesis inhibition 5
• Cross-resistance among tetracyclines is common 5

Epidemiology and Geographic Distribution

The reported incidence of tickborne rickettsial diseases in the United States has increased during the past decade. 1

Geographic Patterns:

• RMSF and E. chaffeensis ehrlichiosis - most commonly reported from Missouri and Oklahoma east to North Carolina and Virginia 1
• RMSF in Arizona - associated with Rhipicephalus sanguineus tick vector, characterized by unusually high incidence and case-fatality rates, particularly among children 1
• R. parkeri rickettsiosis - cases most commonly reported along the Gulf Coast and eastern seaboard 1
• Rickettsia species 364D - all reported cases from California 1
• Anaplasmosis - reported predominantly from northeastern United States, Minnesota, and Wisconsin 1
• EML agent ehrlichiosis - cases identified in persons exposed to ticks in Minnesota and Wisconsin 1

Seasonality:

• Occurrence is seasonal, corresponding with feeding periods of primary tick vectors 1
• Majority of illness occurs during spring and summer months 1
• Anaplasmosis shows bimodal seasonality with peaks in June-July and October 1

Clinical Manifestations

Early signs and symptoms of tickborne rickettsial illnesses are nonspecific, and most cases are misdiagnosed at the patient's first visit for medical care, even in high-awareness areas. 1

Common Presenting Features:

• Fever - most consistent symptom across all rickettsial diseases 2, 3
• Headache - frequently reported 2, 3
• Myalgias and malaise - common accompaniments 3
• Gastrointestinal symptoms - nausea, vomiting, diarrhea, abdominal pain (particularly in ehrlichiosis) 1

Disease-Specific Features:

Rocky Mountain Spotted Fever:

• Classic triad of fever, rash, and reported tick bite is rarely present at initial presentation 1
• Rash present in most patients but can appear late, be atypical, localized, faint, or difficult to recognize in darker-pigmented skin 1
• Thrombocytopenia, increased immature neutrophils, elevated hepatic transaminases, and hyponatremia may be present but are often within or slightly deviated from reference ranges early in illness 1

Ehrlichiosis (E. chaffeensis):

• Symptoms appear median 9 days (range 5-14 days) after infected tick bite 1
• Fever (96%), headache (72%), malaise (77%), myalgia (68%) 1
• Gastrointestinal manifestations prominent: nausea (57%), vomiting (47%), diarrhea (25%) 1
• Rash in approximately one-third of patients, more frequent in children 1
• Central nervous system involvement (meningitis/meningoencephalitis) in approximately 20% 1
• Organisms infect monocytes and tissue macrophages, forming morulae in cytoplasmic vacuoles 1

R. parkeri Rickettsiosis:

• Typically milder than RMSF 1
• First manifestation in nearly all patients is an inoculation eschar 1

Rickettsia species 364D Rickettsiosis:

• Relatively mild illness characterized by eschar or ulcerative skin lesion with regional lymphadenopathy 1
• Fever, headache, myalgia, and fatigue occur 1
• Rash has not been a notable feature 1

Scrub Typhus:

• Fever begins 6-10 days after chigger bite 2
• Eschar (necrotic lesion with black crust) at bite site is characteristic but not always present 2
• Eschar appears as painless, necrotic lesion with black crust surrounded by erythema 2
• Mortality rates up to 4% reported 2

Critical Clinical Considerations

Delay in recognition and treatment is the most important factor associated with risk for death from RMSF and other severe rickettsial diseases. 1

Key Pitfalls:

• Nonspecific early symptoms lead to frequent misdiagnosis 1
• Laboratory findings often within normal ranges early in illness 1
• Rash may be absent, late, or atypical 1
• Classic triad rarely present at initial presentation 1

Diagnosis

Serology remains the mainstay of diagnosis, with indirect immunofluorescence assay as the test of choice. 3, 6

Diagnostic Challenges:

• Reactive antibodies seldom present during early illness 3
• Testing should be performed on both acute-phase and convalescent-phase sera 3
• Treatment should never be delayed while awaiting laboratory confirmation, as delay can lead to severe disease, long-term sequelae, or death 2

Available Tests:

• Microimmunofluorescence (test of choice) 6
• Latex agglutination 6
• Indirect hemagglutination 6
• Immunoperoxidase assay 6
• Enzyme-linked immunosorbent assay (suitable for seroepidemiological studies) 6
• Immunoblot analysis (confirmatory) 6
• Weil-Felix test (low specificity and sensitivity; use only when other tests unavailable) 6

Treatment

Doxycycline is the treatment of choice for adults and children of all ages with suspected rickettsial disease and should be initiated immediately when rickettsial disease is suspected. 1, 2, 5

Dosing Regimens:

Adults:

• Doxycycline 100 mg twice daily (orally or intravenously) 2, 5
• Continue for at least 3 days after fever subsides and until evidence of clinical improvement 2
• Minimum treatment course 5-7 days 2

Children under 45 kg:

• Doxycycline 2.2 mg/kg body weight twice daily (orally or intravenously) 2
• Same duration principles as adults 2

Critical Treatment Principles:

• Early empiric treatment with doxycycline can prevent severe morbidity or death 1
• Patients typically respond to appropriate antibiotics within 24-48 hours 2
• Lack of response within 24-48 hours should prompt consideration of alternative diagnoses 2
• Historical concern about dental staining in children under 8 years should not prevent use of doxycycline for short treatment courses 2
• Severe or complicated disease may require longer treatment courses 2

Alternative Agents:

Chloramphenicol is indicated for serious rickettsial infections when less potentially dangerous drugs are ineffective or contraindicated 7

FDA-Approved Indications for Doxycycline:

Doxycycline is FDA-approved for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae 5

Coinfections

Consider coinfection with other tickborne pathogens, particularly in endemic areas. 1

• Blacklegged tick (Ixodes scapularis) transmits Anaplasma phagocytophilum, Borrelia burgdorferi (Lyme disease), Babesia microti (babesiosis), Borrelia miyamotoi, and deer tick virus 1
• Simultaneous infections with A. phagocytophilum and B. burgdorferi or B. microti have been described 1
• Discerning mixed infection is important as it may affect antimicrobial choice 1

Public Health Implications

Tickborne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children, despite availability of effective antibacterial therapy. 1

Reporting Requirements:

• Report probable and confirmed cases to appropriate public health authorities to assist with surveillance, control measures, and public health education efforts 1

Prevention:

• Advise patients regarding how to avoid tick bites 1
• Awareness of geographic and seasonal risk factors 1
• Recognition of unusual transmission routes (transfusion- or transplantation-associated) 1

Emerging Diseases

Previously undescribed tickborne rickettsial diseases continue to be recognized. 1

• Since 2004, three additional agents described as causes of human disease in the United States: Rickettsia parkeri, Ehrlichia muris-like agent, and Rickettsia species 364D 1
• New or emerging rickettsial diseases include tickborne lymphadenopathy (TIBOLA) and Dermacentor-borne-necrosis-eschar-lymphadenopathy (DEBONEL) related to Rickettsia slovaca infection 8
• Emergence and re-emergence of rickettsial diseases is a serious public health concern in the United States and abroad 9