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Rickettsial Diseases

Chapter 192 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial · Chapter 192

Key Clinical Points

  1. Doxycycline is the first-line treatment for all rickettsial infections, including in children and pregnant women.
  2. Do not wait for a rash to appear before starting treatment; it may be absent (10%) or appear late (day 6+).
  3. Eschar (tache noire) is a hallmark of tick-borne spotted fevers (RMSF, MSF, African tick-bite fever) and rickettsialpox.
  4. Hyponatremia (56% of RMSF cases) and thrombocytopenia (32–52%) are common laboratory findings.
  5. Serologic diagnosis (IFA) is often negative in the first 5–6 days; treat empirically.
  6. Skin biopsy with immunohistochemistry is the gold standard for acute diagnosis (70% sensitive, 100% specific).
  7. Mortality for RMSF is ~3–5%, but higher in children (<2 years) and elderly (>70 years).
  8. Q fever (Coxiella burnetii) is the only rickettsial agent associated with chronic illness.
  9. R. prowazekii and R. rickettsii are significant biothreats due to high infectivity and aerosol transmission potential.
  10. Distinct clinical features like lymphadenopathy help differentiate between types (e.g., Scrub typhus vs. RMSF).

DEFINITION & CLASSIFICATION

• Rickettsial Diseases: Infections caused by organisms of the genera Rickettsia and Orientia (family Rickettsiaceae). • Microbiology: Obligately intracellular, gram-negative coccobacilli. • Transmission: Primarily via tick, mite, flea, or louse vectors; humans are incidental hosts except for louse-borne typhus. • Clinical Progression: Initial 5 days feature fever, headache, and myalgias; later stages may include rash, eschar, pneumonitis, and meningoencephalitis.

1.1 Classification

• Groups: Classified into typhus and spotted fever groups (SFG) based on lipopolysaccharide antigens. • Key Pathogens: ◦ R. rickettsii (RMSF) ◦ R. prowazekii (louse-borne typhus) ◦ Orientia tsutsugamushi (scrub typhus) • Other SFG Organisms: R. conorii, R. typhi, and R. parkeri (less severe disease). • Chronic Infection: Coxiella burnetii is the only rickettsial agent associated with chronic illness.

EPIDEMIOLOGY

• RMSF Distribution: 47 U.S. states, Canada, Mexico, and Central/South America. • Regional Vectors: ◦ Dermacentor ticks (U.S.) ◦ Amblyomma species (South America) ◦ Ixodes holocyclus (Australia) • Other Regions: ◦ Q fever: Global except New Zealand/Antarctica. ◦ Scrub typhus: Eastern Asia, northern Australia, Pacific islands. ◦ Louse-borne typhus: Impoverished regions with poor hygiene. ◦ Rickettsialpox: NYC, Ukraine, Croatia, and Turkey.

2.1 Vector and Reservoir

• Epidemiologic Clues: ◦ Exposure to tick/mite/flea during vector season. ◦ Travel to endemic regions. ◦ Contact with parturient ruminants (Q fever). ◦ Flying squirrel exposure (R. prowazekii). • R. rickettsii Transmission: Maintained via transovarial transmission in ticks; acquired through co-feeding or blood meal from infected mammals.

ETIOLOGY & PATHOPHYSIOLOGY

• Mechanism: Rickettsiae infect endothelial cells → increased vascular permeability. • R. rickettsii Pathogenesis: ◦ Inoculated into dermis after ≥6 hours of tick feeding. ◦ Spreads lymphohematogenously to infect endothelial cells. • Systemic Effects: ◦ Vascular leakage → hypovolemia. ◦ Platelet consumption → thrombocytopenia (32–52% of cases) without DIC. ◦ Noncardiogenic pulmonary edema (12% of cases). ◦ Encephalitis (26–28% of RMSF patients). ◦ Renal: Acute kidney injury via prerenal azotemia. ◦ Hepatic: Common elevation of aminotransferases.

3.1 Pathogenesis

• Endothelial Damage: Primary driver of vascular permeability. • Hemostatic Response: Activation of platelets, thrombin generation, and fibrinolytic system as response to injury. • Severe Disease: May progress to septic shock or fulminant RMSF (50% mortality in patients with comorbidities).

CLINICAL FEATURES

• Early Symptoms (Days 1–3): Fever, headache, myalgia, and malaise (indistinguishable from viral illnesses). • Rash Progression: ◦ Day 1: Present in only 14% of cases. ◦ Day 3: Present in 49% of cases. ◦ Distribution: Starts on wrists/ankles → spreads to trunk/extremities. ◦ Petechiae: Develop in 74% of cases with rash after day 6; present in 41–59% of total cases. ◦ Palm/Sole Involvement: Late development (43%); absent in 18–64% of cases. • Eschar (Tache Noire): ◦ Appearance: At tick/mite bite site before fever onset. ◦ Significance: Hallmark of RMSF, MSF, African tick-bite fever, and rickettsialpox. ◦ Multiplicity: Multiple eschars may occur with group feeding by Amblyomma ticks. • Specific Manifestations: ◦ African tick-bite fever: Eschar + regional lymphadenopathy. ◦ Rickettsialpox: Painless black eschar surrounded by erythematous halo; papulovesicular lesions (Fig. 192-5).

DIFFERENTIAL DIAGNOSIS

• Viral Mimics: Influenza, enteroviral infection, infectious mononucleosis, viral hepatitis, leptopsirosis, typhoid fever. • Bacterial Mimics: Gram-negative sepsis, Streptococcus pyogenes, Salmonella typhi, Bartonella henselae (cat scratch disease), Streptobacillus moniliformis (rat-bite fever). • Hematologic Mimics: Immune thrombocytopenic purpura, thrombotic thrombocytopenic purpura, DIC.

5.1 Clinical Overlap

• Rash-associated Differentials: Rubeola, rubella, meningococcemia, toxic shock syndrome, Kawasaki disease.

DIAGNOSTIC APPROACH

  1. Serology (IFA):
  2. Perform during acute phase.
  3. Note: Often negative in first 5–6 days → do not delay treatment for results.
  4. Criteria: Titer ≥1:128 in acute phase; Convalescent titer >4 imes acute titer is diagnostic.
  5. Skin Biopsy (Gold Standard during acute illness):
  6. Method: Immunohistochemistry to detect intracytoplasmic inclusion bodies in endothelial cells.
  7. Performance: 70% sensitive, 100% specific.
  8. Molecular Testing:
  9. PCR: Detects rickettsial DNA in blood or CSF.
  10. Laboratory Monitoring:
  11. Leukopenia, thrombocytopenia (32–52%), hyponatremia (56%), and elevated CRP/ferritin.

MANAGEMENT & TREATMENT

  1. Pharmacologic Therapy:
  2. Doxycycline (First-line):
  3. Dose: 100 mg PO BID.
  4. Duration: 7–14 days.
  5. Use: Preferred for all rickettsial infections, including children and pregnant women.
  6. Chloramphenicol (Alternative):
  7. Dose: 500 mg IV Q6H.
  8. Duration: 7–14 days.
  9. Contraindications: G6PD deficiency (risk of bone marrow suppression).
  10. Supportive Care:
  11. Intravenous fluids for prerenal azotemia.
  12. Vasopressors (norepinephrine) for hypotension/shock.
  13. Mechanical ventilation for ARDS (seen in 12% of RMSF cases).
  14. Blood transfusions for severe anemia (>30%).

COMPLICATIONS & PROGNOSIS

• Mortality: ◦ RMSF: ~3–5% in postantibiotic era. ◦ High-risk groups: Children (<2 years) and elderly (>70 years). ◦ Fulminant RMSF: 50% mortality (especially in G6PD deficiency). • Sequelae: ◦ Neurologic deficits: 21–26% with encephalitis. ◦ Gangrene requiring amputation: 5–10% of severe cases. ◦ Chronic fatigue syndrome: 15–20% of survivors. • Chronic Q Fever: ◦ Occurs in 1–3% of untreated cases → leads to endocarditis.

SPECIAL POPULATIONS

• Pregnancy: ◦ Doxycycline is preferred over chloramphenicol for RMSF in pregnancy (2nd/3rd trimester) due to higher efficacy and lower risk of fetal complications. • Pediatrics: ◦ Doxycycline is safe in children <8 years for RMSF. ◦ Chloramphenicol may cause gray baby syndrome in neonates. • Recrudescence: ◦ Brill-Zinsser disease: Recrudescent typhus 10–50 years after R. prowazekii infection.

KEY PEARLS & HIGH-YIELD POINTS

• Treatment Timing: Do not wait for rash to appear; early treatment may delay or abort progression. • Diagnostic Markers: ◦ Hyponatremia (56%) and thrombocytopenia (32–52%) are common in RMSF. ◦ Serum IFA is often negative initially; treat empirically. • Differential Diagnosis: Distinguish rickettsialpox from syphilis based on rash pattern. • Table 1 Highlights (Clinical Differentiation): ◦ RMSF: High rash (90%), low eschar (<1%), minimal lymphadenopathy (+). ◦ African tick-bite fever: High rash (50–88%), high eschar (90–94%), significant lymphadenopathy (+++). ◦ Scrub typhus: Moderate rash (50%), moderate eschar (35%), significant lymphadenopathy (+++). • Table 2 Highlights (Chronic Q Fever): ◦ Proven: Coxiella PCR positive OR (IFA ≥1:800/1:1024 AND definite endocarditis or proven large vessel infection). ◦ Probable: IFA ≥1:800/1:1024 AND at least one of (valvulopathy, known aneurysm, suspected osteomyelitis/hepatitis, pregnancy, etc.).

Reference Tables

TABLE 192-1 Features of Selected Rickettsial Infections DISEASE Rocky Mountain spotted fever (RMSF) rickettsii

Harrison's 22e, p.1455

DISEASE ORGANISM TRANSMISSION GEOGRAPHIC
RANGE		 INCUBATION
PERIOD, DAYS		 DURATION,
DAYS		 RASH,
%		 ESCHAR,
%		 LYMPHADENOPATHYa
Rocky Mountain
spotted fever (RMSF)		 Rickettsia
rickettsii		 Tick bite: Dermacentor
andersoni, D. variabilis,
D. similis		 United States 2–14 10–20 90 <1 +
Amblyomma cajennense,
A sculptum, A. patinoi,
A. mixtum, A. aureolatum		 Central/
South America
Rhipicephalus sanguineus Mexico, South
America, United
States
R. conorii Tick bite: R. sanguineus,
R. pumilio		 Southern
Europe, Africa,
Middle East,
central Asia		 5–7 7–14 97 50
African tick-bite
fever		 R. africae Tick bite: A. hebraeum,
A. variegatum		 Sub-Saharan
Africa, West
Indies		 4–10 4–19 50 90 +++
R. parkeri Tick bite: A. maculatum,
A. triste, A. tigrinum, A. ovale		 United States,
South America		 2–10 6–16 88 94
Pacific Coast tick
fever		 Rickettsia ssp
californica		 Tick bite: D. occidentalis United States 3–9 5–14 14 100 +++
R. akari Mite bite: Liponyssoides
sanguineus		 United States,
Ukraine, Turkey,
Mexico, Croatia		 10–17 3–11 100 90
Tick-borne
lymphadenopathy		 R. slovaca,
R. raoultii		 Tick bite: D. marginatus,
D. reticularis		 Europe 7–9 17–180 5 100 ++++
R. felis Flea (mechanism
undetermined):
Ctenocephalides felis		 Worldwide 8–16 8–16 80 15
Epidemic typhus R. prowazekii Louse feces: Pediculus
humanus humanus, fleas
and lice of flying squirrels,
or recrudescence		 Worldwide 7–14 10–18 80 None —
R. typhi Flea feces: Xenopsylla
cheopis, C. felis, others		 Worldwide 8–16 9–18 50 None
Human
monocytotropic
ehrlichiosis (HME)		 Ehrlichia
chaffeensis		 Tick bite: A. americanum,
D. variabilis		 United States 1–21 3–21 26 None ++
E. ewingii Tick bite: A. americanum United States 1–21 4–21 0 None
Unnamed
ehrlichiosis		 E. muris ssp.
eauclairensis		 Tick bite: Ixodes scapularis United States Unknown 3–14 12 None
Anaplasma
phagocytophilum		 Tick bite: I. scapularis,
I. ricinus, I. pacificus,
I. persulcatus,
Haemaphysalis concinna		 United States,
Europe, Asia		 4–8 3–14 Rare None
Unnamed disease A. capra I. persulcatus Northeastern
China, France		 Unknown 11–21 17 9 +
“Candidatus
Neoehrlichia
mikurensis”		 Tick bite: I. ricinus,
I. persulcatus,
Haemaphysalis concinna		 Europe, China ≥8 11–75 10 None
Scrub typhus Orientia
tsutsugamushi		 Mite bite: Leptotrombidium
deliense, others		 Asia, Australia,
Pacific and
Indian Ocean
islands		 9–18 6–21 50 35 +++
O. chuto Mite bite Africa and
Western Asia
Candidatus O.
chiloensis		 Mite bite Chile
Coxiella burnetii Inhalation of aerosols
of infected parturition
material (goats, sheep,
cattle, cats, others),
ingestion of infected milk
or milk products		 Worldwide
except New
Zealand,
Antarctica		 3–30 5–57 4–18% None

TABLE 192-2 Diagnostic Criteria for Chronic Q Fever as Defined by the Dutch Q Fever Consensus Group

Harrison's 22e, p.1463

PROVEN CHRONIC
Q FEVER		 PROBABLE CHRONIC
Q FEVER		 POSSIBLE CHRONIC
Q FEVER
1. Positive Coxiella
burnetii PCR in
blood or tissuea
or
2. IFA ≥1:800 or 1:1024
for C. burnetii phase
I IgG
and
Definite endocarditis
according to the
modified Duke criteria
or
Proven large vessel
or prosthetic infection
by imaging studies
(18FDG-PET, CT, MRI,
or AUS)		 IFA ≥1:800 or 1:1024 for C.
burnetii phase I IgG
AND AT LEAST ONE OF THE
FOLLOWING:
Valvulopathy not meeting the
major criteria of the modified
Duke criteria
Known aneurysm and/or
vascular or cardiac valve
prosthesis without signs of
infection by means of TEE/TTE,
18FDG-PET, CT, MRI, or AUS
Suspected osteomyelitis or
hepatitis as manifestation of
chronic Q fever
Pregnancy
Symptoms and signs of
chronic infection, such as
fever, weight loss, night
sweats, hepatosplenomegaly,
and persistently raised ESR
and CRP
Granulomatous tissue
inflammation, proven by
histologic examination
Immunocompromised state		 IFA ≥1:800 or 1:1024 for
C. burnetii phase I IgG
without manifestations
meeting the criteria
for proven or probable
chronic Q fever