Rickettsial Infections (Typhus, Scrub Typhus, Q Fever)

General Properties

Small, non-motile, Gram-negative coccobacilli. Obligate intracellular. No cell-free growth (only cell lines/animal/egg). Arthropod-transmitted (tick/mite/flea/louse). Target = vascular endothelium.

Classification: Order Rickettsiales — Family Rickettsiaceae (Rickettsia, Orientia) + Family Anaplasmataceae (Ehrlichia, Wolbachia, Anaplasma, Neorickettsia). Coxiella EXCLUDED (inhalational, not arthropod-borne). Bartonella EXCLUDED (grows cell-free, not true obligate intracellular).

Rickettsiae ARE bacteria (once thought virus): Gram-negative wall (poor Gram stain, better Giemsa), DNA+RNA both, binary fission, antibiotic-susceptible, visible light microscopy, retained by bacterial filters.

History: Howard Taylor Ricketts (1911) — RMSF tick transmission. R. prowazekii named for von Prowazek. BOTH died of typhus from their own research.

Rickettsia — 2 Groups

Typhus group vs Spotted fever group.

Antigenic structure: peptidoglycan+LPS+OMP. OMP=species-specific, immunogenic (vaccine+serodiagnosis). LPS=group-specific, cross-reacts with Proteus (basis of Weil-Felix).

Pathogenesis: bite (tick/mite) or rub/scratch contaminated feces (louse/flea). Tick/mite = reservoir too (transovarial transmission). Lymphatics→regional nodes→blood→endothelium (+monocytes for R. akari, O. tsutsugamushi). Adhesion: OmpA/OmpB. Survives lysosomal killing intracellularly. Generation time 9-12hr. Spotted fever group: cell-to-cell via actin polymerization. Others: accumulate until cell lysis.

Comparative Table

Epidemic Typhus (R. prowazekii)

Vector: body louse (Pediculus humanus corporis). Transmission: rub/scratch louse feces, rarely inhalation. Clinical: fever, headache, myalgia, eye discharge, rash (upper trunk d5→generalized, spares face/palms/soles). Severe myalgia. Complications: interstitial pneumonitis, CNS (confusion, coma — “typhus”=Greek “typhos”=smoky/hazy). Fatal 7-40% untreated. Risk: crowded unhygienic (refugee camps, prisons). Zoonotic reservoir: flying squirrels+ectoparasites. Endemic: Africa (Burundi, Rwanda, Ethiopia), S. America. Brill-Zinsser disease: recrudescence years later, latent reactivation (waning immunity).

Endemic/Murine Typhus (R. typhi)

Vector: rat flea (Xenopsylla cheopis), rarely cat flea. Transmission: rub/inhale feces > bite. Reservoir: Rattus species (opossum/cat-flea cycle in S. USA). Milder, rarely fatal. Fever, headache, myalgia, anorexia, trunk rash. India: Shimla, Kashmir, Mumbai, Lucknow, Pune.

RMSF (R. rickettsii)

Vector: Dermacentor(USA), Amblyomma(S. America) tick — ALSO reservoir (+dogs, rodents). Incubation 4-14d. Fever, headache, rash (maculopapular→hemorrhagic, extremities/wrist/ankle+trunk), myalgia, anorexia. Late complications: vascular damage, permeability↑, edema, hemorrhage, DIC, interstitial pneumonitis, CNS. MOST FATAL rickettsial disease. Americas, tick season, children+males.

Indian Tick Typhus (R. conorii)

Vector: Rhipicephalus sanguineus. Similar to RMSF + eschar 50%. Worse in diabetics/alcoholics/heart failure. S. Europe, Africa, S. Asia. India: Nagpur, Jabalpur, Sagar, Pune, Lucknow, Bengaluru, Secunderabad.

Rickettsialpox (R. akari)

Vector: mite (Liponyssoides sanguineus), reservoir = mice. Vesicular rash (confused w/ chickenpox), painless eschar+erythematous halo, regional lymphadenopathy. USA, Ukraine, Turkey, Mexico.

Laboratory Diagnosis

Serology = mainstay.

Weil-Felix: heterophile tube agglutination, cross-reactivity with Proteus (OX19, OX2, OXK). After 5-7d fever. Titer 1:80 = possible.

• Epidemic/endemic typhus: OX19 (±OX2)
• Spotted fever: OX19+OX2
• Scrub typhus: OXK
• NEGATIVE: rickettsialpox, Q fever, ehrlichiosis, bartonellosis False+: underlying Proteus (fix: 4-fold paired rise). False-: prozone (fix: serial dilution). Always confirm with specific test.

Specific: IFA = gold standard (Ab after 7-10d, titer≥1:64 significant). IgM-capture ELISA = early diagnosis (<1wk).

Other: cutaneous biopsy histology, isolation (Vero/HeLa cell line, egg yolk sac, guinea pig — needs BSL-3), Neil-Mooser reaction (OBSOLETE), PCR (surface antigen gene, 16S rRNA, Omp — best blood in first 7-10d).

Treatment: Doxycycline (1-5d) DOC for ALL rickettsial illness. Chloramphenicol = alternative. Prevention: vector control, rodent control, hygiene. NO VACCINE available.

Scrub Typhus (Orientia tsutsugamushi)

Formerly Rickettsia. Genetically different, NO LPS layer. Named for scrub vegetation habitat (also sandy/semi-arid/mountain-desert). Vector: trombiculid mites (L. akamushi-Japan, L. deliensis-India). LARVAE (“chiggers”) only stage feeding on humans = “chiggerosis.” Transovarial maintenance.

Clinical: Classic triad (eschar+regional LAD+maculopapular rash) in only 40-50%. Early nonspecific: fever, headache, myalgia, cough, GI symptoms. Rare late: encephalitis, interstitial pneumonia.

Epidemiology: MOST WIDESPREAD rickettsial disease. Zoonotic tetrad: trombiculid mites + small mammals + secondary scrub vegetation + wet season. “Tsutsugamushi triangle”: Japan-Russia(N) to Australia(S) to Pakistan(W), includes India. India: COMMONEST rickettsial disease. Sub-Himalayan belt, Bihar, Rajasthan, Maharashtra, Karnataka, TN, Pondicherry, Kerala. Rural→urban shift occurring.

Diagnosis: Primary infection — IgM end wk1, IgG end wk2. Reinfection — IgG by day 6 (IgM variable). Weil-Felix (nonspecific, OXK). IFA (specific, gold standard). ELISA (56-kDa recombinant protein, cost-effective IFA alternative). PCR (56-kDa, 47-kDa, 16S rRNA genes).

Treatment: Doxycycline. Alt: chloramphenicol/azithromycin.

Ehrlichiosis (Family Anaplasmataceae)

4 genera: Ehrlichia, Wolbachia, Anaplasma, Neorickettsia. Vertebrate reservoirs, target hematopoietic cell vacuoles.

Pathogenic species:

• E. chaffeensis — Human monocytic ehrlichiosis (mononuclear phagocytes)
• E. ewingii — Human granulocytic ehrlichiosis (neutrophils)
• A. phagocytophilum — Human granulocytic anaplasmosis (neutrophils)
• N. sennetsu — Human lymphocytic ehrlichiosis (lymphocytes) — UNIQUE: transmitted by eating infected fluke-carrying FISH, not tick

USA (except N. sennetsu = Japan/Malaysia). Reservoirs: white-tailed deer, dogs. Clinical: fever, headache, myalgia, arthralgia, cough, pharyngitis, LAD, diarrhea, N/V, abdominal pain, mental status change. Inclusions: elementary body→initial body→MORULA (mulberry-like). Detected in neutrophils, Giemsa blood film, 20-75%. Treatment: Doxycycline DOC.

Q Fever (Coxiella burnetii)

Obligate intracellular, NOT arthropod-borne (excluded from Rickettsiaceae). “Query”→Q fever, later named for Cox+Burnet. Zoonotic: cattle, sheep, goats. Transmission: INHALATION of contaminated dust (main route), rarely contaminated milk. Endemic almost everywhere except NZ+Antarctica. India: Rajasthan, Punjab, Haryana, Delhi.

Incubation 3-30d. Acute Q fever: hepatitis, interstitial pneumonia, fever, CNS, pericarditis/myocarditis. Chronic Q fever: months-2-3yr later, 5% of cases, = ENDOCARDITIS.

Diagnosis: small pleomorphic Gram-negative coccobacillus. Extremely fastidious — isolation needs BSL-3 (shell-vial, buffy coat/tissue). IFA = method of choice. Phase I + Phase II LPS antigens. Acute = Phase II titer HIGHER. Chronic = Phase I titer HIGHER. PCR: direct DNA detection.

Treatment: Acute = doxycycline 14 days (quinolones also work). Chronic = + hydroxychloroquine (alkalinizes phagolysosome, makes doxycycline bactericidal).

Prevention: Q-Vax (inactivated whole-cell, licensed Australia, occupational workers). Animal husbandry (excreta disposal). Flash pasteurization (72°C/20sec + rapid cooling).

Bartonellosis

Fastidious, facultative intracellular, Gram-negative. Invades mammalian cells+RBC. 3 species matter:

B. henselae (cat scratch/bite):

• Cat-scratch disease: regional LAD + painless papule at scratch site. Rare: hepatitis, splenitis, retinitis
• Bacillary angiomatosis: angioproliferative skin/organ lesions
• Bacillary peliosis: angioproliferative liver/spleen

B. quintana (louse):

• Trench fever: WWI epidemic, mild 5-day illness recurring q5days (“5-day fever”). Re-emerging USA.
• Others: bacillary angiomatosis, chronic bacteremia, endocarditis

B. bacilliformis (sandfly, Lutzomyia): BIPHASIC disease

• Oroya fever/Carrion’s disease: initial bacteremic systemic illness ±anemia
• Verruga peruana: late cutaneous vascular lesions
• Others: bacteremia, endocarditis

Diagnosis: blood/LN/skin biopsy. Warthin-Starry silver stain or IF (LN smears). Culture (blood agar, 37°C, 12-15 days). IFA/EIA (species-specific). PCR (16S rRNA).

Treatment: Cat-scratch disease = NOT routinely treated (azithromycin if extensive LAD). Bacillary angiomatosis = erythromycin/doxycycline 3 months.

General Properties

Rickettsiae are small, non-motile, Gram-negative coccobacilli sharing four defining features: they are obligate intracellular organisms; they cannot grow on artificial cell-free media (only in cell lines, or by animal/egg inoculation); they are transmitted by arthropod vectors (tick, mite, flea, louse); and they infect vascular endothelial cells as their final target.

Classification: the order Rickettsiales has two families — Rickettsiaceae (genera Rickettsia and Orientia) and Anaplasmataceae (Ehrlichia, Wolbachia, Anaplasma, Neorickettsia). Coxiella and Bartonella were formerly grouped here but are now excluded: Coxiella is not arthropod-borne (it spreads by inhalation), and Bartonella is not a true obligate intracellular parasite (it can grow in cell-free media) and differs genetically.

Rickettsiae versus viruses: once thought viral because of their small size and obligate intracellular life, rickettsiae are confirmed bacteria — they have a Gram-negative cell wall (though they stain poorly with Gram stain, better with Giemsa), contain both DNA and RNA, multiply by binary fission, are antibiotic-susceptible, are visible by light microscopy, and are retained by bacterial filters.

History: named after Howard Taylor Ricketts (1911), who discovered tick transmission of Rocky Mountain spotted fever; R. prowazekii is named for von Prowazek. Both Ricketts and von Prowazek died of typhus contracted during their own research.

Rickettsia Infections

Rickettsia splits into a typhus group and a spotted fever group, distinguished by clinical presentation, vector, and serology (see table).

Antigenic structure: the cell wall carries peptidoglycan, LPS, and outer membrane proteins (OMPs). OMP antigens are species-specific and highly immunogenic (useful for vaccines and specific serodiagnosis); LPS antigens are group-specific and cross-react with certain Proteus strains — the basis of the Weil-Felix test.

Pathogenesis: transmission occurs by arthropod bite (tick, mite) or by rubbing/scratching the vector’s contaminated faeces into abraded skin (louse, flea) — ticks and mites additionally serve as environmental reservoirs via transovarial transmission. Organisms spread via lymphatics to regional nodes, then bloodstream, targeting vascular endothelium everywhere (plus monocytes specifically for R. akari and O. tsutsugamushi). Adhesion uses surface proteins OmpA/OmpB; after phagocytosis, rickettsiae survive intracellularly by resisting lysosomal killing, multiplying slowly (generation time 9–12 hours). Spotted fever group rickettsiae spread cell-to-cell via actin polymerization; other rickettsiae instead accumulate until the host cell lyses.

Comparative Table

Epidemic (Louse-borne) Typhus — R. prowazekii

Vector: human body louse (Pediculus humanus corporis). Transmission: rubbing/scratching louse-faeces-contaminated skin, rarely by inhalation (lab or bioterrorism exposure). Acute febrile illness with headache, myalgia, eye discharge, and rash beginning on the upper trunk around day 5, spreading to become generalized (sparing face, palms, soles); myalgia is often severe. Complications: interstitial pneumonitis, CNS involvement (mental confusion, coma — the word “typhus” itself derives from Greek typhos, “smoky/hazy,” describing this mental state). Fatal in 7–40% if untreated. Outbreaks occur with rising louse populations in unhygienic, crowded settings (refugee camps, prisons). Zoonotic maintenance: eastern flying squirrels and their ectoparasites. Endemic in Africa (Burundi, Rwanda, Ethiopia) and South America. Brill-Zinsser disease is a recrudescent illness years after acute infection — R. prowazekii persists latently and reactivates as immunity wanes, causing sporadic cases or outbreaks.

Endemic (Flea-borne/Murine) Typhus — R. typhi

Vector: rat flea (Xenopsylla cheopis), rarely cat flea. Transmission: rubbing/inhaling dried flea faeces, less often direct bite. Reservoir: Rattus species (opossum/cat-flea cycle prominent in southern USA). Milder, rarely fatal version of epidemic typhus — fever, headache, myalgia, anorexia, trunk-predominant rash. Endemic worldwide in warm, rat-infested coastal areas; reported from Shimla, Kashmir, Mumbai, Lucknow, Pune in India.

Rocky Mountain Spotted Fever — R. rickettsii

Vector: Dermacentor (USA), Amblyomma (South America) ticks, which also serve as reservoirs (alongside dogs, small rodents). Incubation 4–14 days. Acute, potentially fatal disease — fever, headache, rash (starting maculopapular on extremities/wrists/ankles and trunk, becoming hemorrhagic), myalgia, anorexia. Late complications: vascular damage, permeability increase, oedema, haemorrhage, DIC, interstitial pneumonitis, CNS involvement. The most fatal rickettsial disease. Endemic in high-tick-density areas of the Americas, peaking in tick season, more common in children and males.

Indian Tick Typhus — R. conorii

Vector: Rhipicephalus sanguineus tick bite. Clinically similar to RMSF, with an eschar at the bite site in 50% of cases; more severe in diabetics, alcoholics, and heart failure patients. Widespread across southern Europe, Africa, southern Asia — in India, reported from Nagpur, Jabalpur, Sagar, Pune, Lucknow, Bengaluru, Secunderabad.

Rickettsialpox — R. akari

Vector: mite bite (Liponyssoides sanguineus), reservoir mice. Distinguished from other rickettsioses by vesicular rash (often mistaken for chickenpox, hence the name), a painless eschar with erythematous halo, and regional lymphadenopathy. Endemic in USA, Ukraine, Turkey, Mexico.

Laboratory Diagnosis of Rickettsiosis

Serology is the mainstay, split into nonspecific and specific tests.

Weil-Felix test: a heterophile tube agglutination test exploiting antigenic cross-reactivity between rickettsial alkali-stable LPS and certain Proteus strains (OX19, OX2, OXK). Cheap and useful despite modest sensitivity/specificity. Performed only after 5–7 days of fever; a titre of 1:80 suggests possible infection. Pattern: epidemic/endemic typhus — mainly OX19 (sometimes OX2); tick-borne spotted fever — both OX19 and OX2; scrub typhus — OXK. Negative in rickettsialpox, Q fever, ehrlichiosis, and bartonellosis. False positives occur with underlying Proteus infection (a fourfold paired-sera rise is more meaningful than one high titre); false negatives from prozone (overcome by serial dilution). Being nonspecific, a positive result should always be confirmed.

Specific tests: indirect immunofluorescence assay (IFA) is the gold-standard confirmatory test (antibodies appear only after 7–10 days; titre ≥1:64 significant); IgM-capture ELISA is useful for early diagnosis (<1 week) with excellent sensitivity/specificity.

Other methods: histological examination of a cutaneous rash biopsy (possible even during acute illness); isolation (cell lines — Vero, HeLa; egg yolk sac; guinea pig inoculation — requires BSL-3 given high infectivity); the historical Neil-Mooser reaction (guinea pig speciation, now obsolete); and PCR/real-time PCR targeting major surface antigen genes, 16S rRNA, or Omp genes (best from blood in the first 7–10 days, when rickettsemia is present).

Treatment: doxycycline (1–5 days) is the drug of choice for essentially all rickettsial illnesses; chloramphenicol is the alternative.

Prevention: vector control (insecticides), rodent/animal control, personal hygiene — no vaccine is currently available.

Scrub Typhus (Orientia tsutsugamushi)

Formerly classified under Rickettsia, Orientia differs genetically and lacks the LPS layer other rickettsiae carry. Named for its association with scrub vegetation (low trees/bushes), though sandy, semi-arid, and mountain-desert areas can also be endemic. Vector: trombiculid mites (Leptotrombidium akamushi in Japan, L. deliensis in India) — only the larval stage (“chiggers”) feeds on humans, hence the alternate name chiggerosis; mites maintain the organism transovarially.

Clinical: the classic triad — eschar at the bite site, regional lymphadenopathy, maculopapular rash — appears in only 40–50% of cases; nonspecific early symptoms (fever, headache, myalgia, cough, GI symptoms) are common. Rare late complications: encephalitis, interstitial pneumonia (from vascular injury).

Epidemiology: the most widespread rickettsial disease. Maintenance needs a zoonotic tetrad: trombiculid mites, small mammals (field mice, rats, shrews), secondary scrub vegetation/forest, and a wet season (mite egg-laying). Endemic to the “tsutsugamushi triangle” (Japan-Russia in the north, Australia in the south, Pakistan in the west), including India, where it’s the commonest rickettsial disease, historically rural but increasingly reported from urban areas too — sub-Himalayan belt, Bihar, Rajasthan, Maharashtra, Karnataka, Tamil Nadu, Pondicherry, Kerala.

Diagnosis: in primary infection, IgM appears by end of week 1, IgG by end of week 2; in re-infection, IgG is detectable by day 6 (IgM variable). Weil-Felix (nonspecific, OXK); IFA (specific, gold standard); ELISA using 56-kDa recombinant surface protein (cost-effective IFA alternative). Molecular: PCR targeting 56-kDa, 47-kDa, or 16S rRNA genes.

Treatment: doxycycline; chloramphenicol or azithromycin as alternatives.

Ehrlichiosis (Family Anaplasmataceae)

Four obligate intracellular genera — Ehrlichia, Wolbachia, Anaplasma, Neorickettsia — residing in vertebrate reservoirs and targeting vacuoles within hematopoietic cells. Pathogenic species: Ehrlichia chaffeensis (human monocytic ehrlichiosis, infects mononuclear phagocytes), Ehrlichia ewingii (human granulocytic ehrlichiosis, infects neutrophils), Anaplasma phagocytophilum (human granulocytic anaplasmosis, neutrophils), Neorickettsia sennetsu (human lymphocytic ehrlichiosis, lymphocytes — uniquely transmitted by eating infected fluke-carrying fish, rather than by tick).

Prevalent in the USA (except N. sennetsu, seen in Japan/Malaysia), with animal reservoirs like white-tailed deer and dogs. Acute febrile illness — headache, myalgia, arthralgia, cough, pharyngitis, lymphadenopathy, diarrhoea, nausea, vomiting, abdominal pain, altered mentation. Inside the phagosome, organisms progress through elementary body → initial body → mulberry-like inclusion clusters called morulae, detectable in neutrophils by Giemsa-stained blood film in 20–75% of cases. Doxycycline is the drug of choice.

Q Fever (Coxiella burnetii)

An obligate intracellular organism (though not arthropod-transmitted, hence excluded from Rickettsiaceae proper), named “Q” (Query) fever before its cause was identified, later renamed for discoverers Cox and Burnet. Zoonotic — humans acquire it from cattle, sheep, goats, most commonly by inhaling contaminated dust (from soil soiled with animal urine/faeces), rarely by ingesting contaminated milk. Endemic almost everywhere except New Zealand and Antarctica; in India, reported from Rajasthan, Punjab, Haryana, Delhi.

Incubation 3–30 days. Acute Q fever: hepatitis, interstitial pneumonia, fever, CNS involvement, pericarditis/myocarditis. Chronic Q fever develops months to 2–3 years later in ~5% of cases, presenting as endocarditis.

Diagnosis: C. burnetii is a small pleomorphic Gram-negative coccobacillus, extremely fastidious — isolation (shell-vial technique from buffy coat/tissue) requires BSL-3. IFA is the antibody method of choice, detecting antibodies against Phase I and Phase II LPS antigens: acute Q fever shows a higher Phase II titre, chronic Q fever a higher Phase I titre. PCR detects DNA directly in tissue.

Treatment: acute Q fever — doxycycline for 14 days (quinolones also effective); chronic Q fever — hydroxychloroquine added to alkalinize the phagolysosome, rendering doxycycline bactericidal. Prevention: an inactivated whole-cell vaccine (Q-Vax) is licensed in Australia for occupationally exposed workers; good animal husbandry (proper excreta disposal); flash pasteurization of milk (72°C for 20 seconds, then rapid cooling).

Bartonellosis

Bartonella species are fastidious, facultative intracellular Gram-negative bacteria capable of invading mammalian cells and RBCs. Three species matter clinically:

B. henselae (transmitted by cat scratch/bite): cat-scratch disease (regional lymphadenopathy, painless papule at the scratch site; rarely hepatitis, splenitis, retinitis); bacillary angiomatosis (angioproliferative skin/organ lesions); bacillary peliosis (angioproliferative liver/spleen disease).

B. quintana (transmitted by louse): trench fever — historically epidemic among WWI soldiers, a mild 5-day febrile illness recurring every 5 days (“five-day fever”), now re-emerging in the USA; also causes bacillary angiomatosis, chronic bacteremia, and endocarditis.

B. bacilliformis (transmitted by sandfly, Lutzomyia): a biphasic disease — Oroya fever/Carrion’s disease (initial bacteremic, systemic illness, ± anaemia) followed by verruga peruana (late cutaneous vascular lesions); also bacteremia and endocarditis.

Diagnosis: specimens — blood, lymph node, or skin biopsy. Warthin-Starry silver stain or immunofluorescence on lymph node smears; culture on blood agar (37°C, 12–15 days); IFA/EIA antibody detection (species-specific); PCR (16S rRNA). Treatment: cat-scratch disease is not routinely treated (azithromycin for extensive lymphadenopathy); bacillary angiomatosis needs erythromycin or doxycycline for 3 months.

Short Notes (5)

Multiple Choice Questions (1)