Clinical presentation of BZD resembles a mild case of epidemic typhus and most patients suffering from BZD have a medical history of the latter. While epidemic typhus has an incubation period of about 10 days, the latency period between epidemic typhus and BZD may encompass decades. In most cases, a precise cause of reactivation cannot be determined and patients present with sudden onset of unspecific symptoms like malaise, fatigue, fever, chills, headaches, myalgia, arthralgia and rash [4] [7]. Body temperature may rise above 40 °C, but lower-grade fever has also been registered. Although febrile exanthema is often cited as a characteristic symptom of BZD, dermatological symptoms may be absent.

In epidemic typhus, complications may arise from involvement of the central nervous system or internal organs. Although such symptoms are rarely observed in BZD patients, affected individuals may eventually present with the following [10]:

• Meningitis, encephalitis, reduced awareness
• Symptoms of hepatic or renal dysfunction
• Cardiac failure
• Pneumonia
• Gangrene due to severe vasculitis

• Fever

  fever [tick-borne rickettsioses] A77.0 Spotted fever due to Rickettsia rickettsii A77.1 Spotted fever due to Rickettsia conorii A77.2 Spotted fever due to Rickettsia siberica A77.3 Spotted fever due to Rickettsia australis Reimbursement claims with a [icd10data.com]

  Tick-borne Rickettsia rickettsii Rocky Mountain spotted fever Rickettsia conorii Boutonneuse fever Rickettsia japonica Japanese spotted fever Rickettsia sibirica North Asian tick typhus Rickettsia australis Queensland tick typhus Rickettsia honei Flinders [infogalactic.com]

  Brill-Zinsser disease - an endogenous reinfection associated with the "carrier state" in persons who previously had epidemic typhus fever. [medical-dictionary.thefreedictionary.com]

• Fatigue

  Complaints mainly comprise fatigue, fever, chills, headaches, myalgia, arthralgia and rash. Treatment consists in administration of tetracycline antibiotics for one to two weeks. [symptoma.com]

  A 69-year-old man living in France sought care from his general practitioner on March 7, 2011, after 2 days of high-grade fever (40°C) associated with headache, myalgia, fatigue, and mild cough. [wwwnc.cdc.gov]

  —I have an idea that agitation does it as much harm as fatigue” (8 September 1816); “I am almost entirely cured of my rheumatism; just a little pain in my knee now & then” (20 February 1817); “I have still a tendency to Rheumatism” (26 March 1817). [jasna.org]

• Arthralgia

  Complaints mainly comprise fatigue, fever, chills, headaches, myalgia, arthralgia and rash. Treatment consists in administration of tetracycline antibiotics for one to two weeks. [symptoma.com]

  […] cough arthalgia myalgia photophobia delirium murine or endemic typhus abdominal pain diarrhea backache headache extremely high fever (105-106 F) may last for up to two weeks dull, red rash begins on the trunk and spreads peripherally hacking, dry cough arthralgia [medbullets.com]

  He also complained of malaise, myalgia and arthralgia for the same duration but denied any urinary, respiratory or abdominal symptoms. [bmcresnotes.biomedcentral.com]

  In addition, unspecific clinical manifestations (relative frequency given in brackets) might be associated with epidemic typhus such as abdominal pain (60%), nausea (32%), arthralgia (50%), cough (38%) and less frequently conjunctivitis. [ecdc.europa.eu]

• Eczema

  Non-infected members of the household should pay special attention to areas of the skin that have been injured, such as cuts, scrapes, insect bites, areas of eczema, and rashes. These areas should be kept clean and covered to prevent infection. [enacademic.com]

• Headache

  This disease is characterized by the sudden onset of intense headache, malaise, and generalized myalgia followed by the formation of a macular skin eruption and vascular and neurologic disturbances. [dianamossop.com]

  Symptoms are prolonged high fever, intractable headache, and a maculopapular rash. Epidemic typhus is a rickettsial disease. [merckmanuals.com]

  Complaints mainly comprise fatigue, fever, chills, headaches, myalgia, arthralgia and rash. Treatment consists in administration of tetracycline antibiotics for one to two weeks. [symptoma.com]

  Fuji p re sents to the emergency clinic with "the worst headache of his life," accompanied by fevers, chills, malaise, photophobia, and a macular/papular rash spread across his trunk, face, and upper extremities. [medbullets.com]

  The rash is often evanescent or absent. [5] The following may also be noted: severe headache, rash, chills, muscle pain, kidney dysfunction, altered mental status, cough, delirium, photophobia and joint pain. [6] Diagnosis Physical examination and medical [library.everyonehealthy.com]

As per definition, BZD can only been diagnosed in patients with a medical history of epidemic typhus. Most commonly, the latter has been contracted in times and regions of war [11] or - in more recent cases - upon previous contact with flying squirrels [4]. However, in 2011, BZD has been diagnosed in a Moroccan man who lived in France and who claimed no previous exposure to R. prowazekii. Although BZD itself may presumably follow a subclinical course [12], this is not typical for epidemic typhus. In any case, thorough anamnesis is one of the mainstays of BZD diagnosis. Patients should be queried regarding periods they lived under precarious hygienic conditions, regarding previous infestation with parasites, contact to people who suffered from epidemic typhus or BZD and contact to vectors.

Reactivation of latent infection with R. prowazekii is associated with a rapid increase in serum immunoglobulin G antibody titers to this pathogen. Thus, any patient presenting with a history of epidemic typhus and symptoms consistent with BZD should undergo serological testing. However, positive results can not be expected until 10 days after symptom onset and if a patient is suspicious for BZD, antibiotic treatment should start earlier. Of note, antibody titers peak about one month later and should eventually decrease if the patient responds to therapy. Timely initiation of therapy significantly improves the outcome and reduces the risk of an epidemic.

Isolation of bacteria from blood samples and cultivation are challenging tasks. Nevertheless, DNA isolated from buffy coats may be used for molecular biological testing and polymerase chain reactions designed for detection of R. prowazekii DNA may yield positive results before an antibody response becomes detectable [13].

• Rickettsia Prowazekii

  The agent that causes epidemic typhus (Rickettsia prowazekii) remains viable for many years and then when host defenses are down, it is reactivated causing recurrent typhus. [medicine.academic.ru]

  exanthematisch; vlektyfus, klassiek; vlektyfus, luizen; tabardillo, luizen; vlektyfus, prowazekii; Rickettsia prowazekii, vlektyfus, rickettsiose; Rickettsia prowazekii, tabardillo; door luizen overgebracht, vlektyfus; Rickettsia prowazekii, vlektyfus [fpnotebook.com]

  From Etiology endogenous reinfection with Rickettsia prowazekii associated with a carrier state in persons previously with epidemic typhus ( recrudescent typhus ) Clinical-manifestations may occur 30-50 years after the original infection Notes 1st described [anvita.info]

  prowazekii A75.0 ICD-10-CM Diagnosis Code A75.0 Epidemic louse-borne typhus fever due to Rickettsia prowazekii 2016 2017 2018 2019 Billable/Specific Code Applicable To Classical typhus (fever) Epidemic (louse-borne) typhus recrudescent A75.1 exanthematicus [icd10data.com]

• Vibrio Parahaemolyticus

  […] cholerae Cholera Vibrio vulnificus Vibrio parahaemolyticus Vibrio alginolyticus Plesiomonas shigelloides Pseudomonadales Pseudomonas aeruginosa Pseudomonas infection Moraxella catarrhalis Acinetobacter baumannii Xanthomonadaceae Stenotrophomonas maltophilia [vikipedin.com]

• Brucella Abortus

  abortus Brucellosis Bartonellaceae Bartonellosis : Bartonella henselae Cat-scratch disease Bartonella quintana Trench fever Either B. henselae or B. quintana Bacillary angiomatosis Bartonella bacilliformis Carrion's disease, Verruga peruana β Neisseriales [vikipedin.com]

• Citrobacter Koseri

  koseri / Citrobacter freundii Lac− H2S+ Salmonella enterica Typhoid fever, Paratyphoid fever, Salmonellosis H2S− Shigella dysenteriae / sonnei / flexneri / boydii Shigellosis, Bacillary dysentery Proteus mirabilis / Proteus vulgaris Yersinia pestis Plague [vikipedin.com]

  koseri / Citrobacter freundii Lac- H2S+ Salmonella enterica Typhoid fever, Paratyphoid fever, Salmonellosis H2S- Shigella dysenteriae / sonnei / flexneri / boydii Shigellosis, Bacillary dysentery Proteus mirabilis / Proteus vulgaris Yersinia pestis Plague [infogalactic.com]

• Kingella

  Carrion's disease, Verruga peruana β Neisseriales M+ Neisseria meningitidis/meningococcus Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M− Neisseria gonorrhoeae/gonococcus Gonorrhea ungrouped: Eikenella corrodens / Kingella [vikipedin.com]

  Carrion's disease, Verruga peruana β Neisseriales M+ Neisseria meningitidis/meningococcus Meningococcal disease, Waterhouse–Friderichsen syndrome, Meningococcal septicaemia M- Neisseria gonorrhoeae/gonococcus Gonorrhea ungrouped: Eikenella corrodens / Kingella [infogalactic.com]

Drug therapy with antibiotics pertaining to the tetracycline class of antimicrobials is the treatment of choice. Patients are administered a daily dose of 200 mg doxycycline for up to two weeks. Fever should resolve within the first week of therapy, and full resolution is to be expected after two weeks.

Such treatment is contraindicated in pediatric patients and pregnant women. Here, application of a single dose of 100 or 200 mg doxycycline, respectively, is recommended. This therapeutic approach has shown satisfying results in an outbreak of epidemic typhus in Burundi [14].

In case of epidemics and limited resources, single-dose treatment with doxycycline is often the only chance to reduce morbidity and mortality and to prevent further spread of the disease.

Azithromycin has proven ineffective to treat BZD [15], but chloramphenicol may constitute an alternative if no other drugs are available.

Whereas epidemic typhus is associated with high morbidity and mortality if left untreated - the World Health Organization reports fatality rates of up to 20% -, BZD follows a milder course. However, pathogens may reach the central nervous system and internal organs during bacteremia, cause neurologic, hepatic and renal damage, and if adequate treatment is not provided, the disease is still potentially fatal. This applies particularly to immunocompromised patients and if a weakened immune system triggers reactivation of rickettsiosis, immunodeficiencies may not be uncommon among BZD patients.

Nevertheless, if effective antibiotics are available and administered in a timely manner, prognosis is very good.

Etiologic agent of epidemic typhus and BZD is R. prowazekii, an obligate intracellular bacterium pertaining to the same genus as those pathogens causing Rocky Mountain spotted fever and Mediterranean spotted fever. Several strains have been identified that differ in virulence; whereas epidemic typhus and BZD are potentially fatal diseases, an avirulent strain that could eventually be used for vaccine development has been described, too [2].

For a long time, R. prowazekii has been assumed to be transmitted via the feces of the human body louse (Pediculus humanus corporis). However, recently published results imply that other species of lice may also transmit the etiologic agent of BZD to men. In this line, head lice (Pediculus humanus capitis) and pubic lice (Phthirus pubis) should be considered as possible vectors, although experimental data regarding the latter is very scarce [3].

Generally, the parasite contracts R. prowazekii while feeding on an infected human. Accordingly, people suffering from epidemic typhus or an acute bout of BZD are considered the main reservoir of the bacterium. However, due to improvements in sanitation and general hygiene, parasitic loads have significantly decreased. The efficacy of hygiene measures is enhanced by the fact that lice infected with R. prowazekii die within weeks, thereby further reducing the risk of transmission. In developed countries, human-to-human transmission via lice is therefore much less likely than decades ago.

In North America, R. prowazekii has been isolated from flying squirrels and while a relation between zoonotic infection with R. prowazekii and typhus has been described a long time ago, the first case of BZD due to zoonotic infection has only been reported in 2010 [4]. Today, the southern flying squirrel (Glaucomys volans) is considered the main reservoir of R. prowazekii in these geographical regions.

Little is known about the actual triggers of BZD, i.e., about conditions that cause an reactivation of persistent bacteria. Stress or other environmental factors that weaken the immune system have been proposed as possible causes of recrudescent typhus.

Epidemic typhus is a major health concern in regions of war and famine, in areas where many people live under poor hygienic conditions in restricted spaces. These are the precise circumstances that favor parasitic infestation and transmission of vector-borne diseases like rickettsioses.

In recent years, cases of epidemic typhus and/or BZD have been reported in:

• In the eastern United States, in areas where flying squirrels may be encountered [5]
• In highland areas of South America, mainly in Peru [6]
• In distinct African countries, e.g., in Morocco, Algeria, Ethiopia, Uganda, Rwanda and Burundi
• In Russia

People may import R. prowazekii into previously unaffected regions, as has recently been reported in France [7]. In conditions of cold, hunger and overcrowding - conditions that characterize many refugee camps throughout the world - epidemics may easily spread.

R. prowazekii is transmitted by lice that feed on human blood although the bacterium is not directly injected into circulation. The pathogen inhabits the insect's digestive tract and is excreted with its feces. The insect's bite causes pruritus and if the host scratches, they may move excrements into the wound. Besides, Chagas disease, another vector-borne disease, is transmitted similarly.

Rickettsemia ensues upon infection with R. prowazekii. This pathogen mainly targets endothelial cells, thus causing a generalized vasculitis and systemic symptoms. Subsequent infiltration by leukocytes as well as release of proinflammatory cytokines and chemokines presumably plays a major role in epidemic typhus and BZD pathogenesis [8].

Considerable knowledge gaps remain regarding the pathomechanisms behind latency and reactivation of R. prowazekii. Endothelial cells don't necessarily serve as a reservoir of bacteria in patients suffering from latent infection with R. prowazekii and only recently, adipose tissue has been proposed to fulfill this role [9]. Of note, latent infections have not been observed in any other Rickettsia species.

In general, adequate personal hygiene should suffice to prevent infestation with lice. Clothes and bedding should be changed and washed regularly. In case of louse infestation, insecticides such as permethrin should be used to reduce the parasitic load. Repeated delousing procedures may be required in endemic regions.

In affected regions of North America, contact with flying squirrels should be avoided.

During epidemics, administration of single doses of doxycycline is the most effective preventive measure. The antibiotic should be applied in all clinically suspected cases of epidemic typhus.

Brill-Zinsser disease (BZD) is caused by latent infection with Rickettsia prowazekii (R. prowazekii), causative agent of epidemic typhus. This pathogen is transmitted via the feces of infected lice, mainly those of body lice. Consequently, infestation with those parasites is a prerequisite for contracting epidemic typhus and BZD. In developed countries, extensive implementation of hygiene measures has considerably reduced parasitic loads, and incidence rates of epidemic typhus and BZD have been constantly decreasing. Today, both are considered rare diseases in industrialized nations. However, case reports from less developed regions in America, Africa and Asia emphasize that this disease still needs to be considered in clinical practice [1]. This particularly applies to physicians who practice in affected regions and whose access to antibiotics may be restricted at times.

BZD may manifest months or many years after suffering from epidemic typhus. If the latter is not accordingly treated or drug therapy does not suffice for a complete elimination of R. prowazekii, bacteria may persist in the patient's body and the disease may be reactivated much later. BZD typically follows a milder course than epidemic typhus, although symptoms are similar. Complaints mainly comprise fatigue, fever, chills, headaches, myalgia, arthralgia and rash. Treatment consists in administration of tetracycline antibiotics for one to two weeks. If adequate treatment is provided, the patient's prognosis is very good.

Epidemic typhus is an infectious disease caused by Rickettsia prowazekii; it is transmitted via the feces of the human body louse. The parasite bites its human host, excretes bacteria, and if the affected individual scratches, those pathogens may reach the blood flow. Consequently, infestation with those parasites is a prerequisite for contracting epidemic typhus. Some patients overcome epidemic typhus but their immune system is unable to eliminate all bacteria. Rickettsia may persist for years and the infection may recrudesce much later. Reactivation of a latent infection with Rickettsia prowazekii is termed Brill-Zinsser disease (BZD).

People who live under poor hygienic conditions, in overcrowded spaces, in regions marked by war and hunger, are much more prone to suffer from infestation with lice. In developed countries, extensive implementation of hygiene measures has considerably reduced parasitic loads, and case numbers of epidemic typhus and BZD have been constantly decreasing. However, these diseases are still considerable health concerns in regions where poor socioeconomic conditions prevail.

Of note, in the eastern United States and determined parts of Mexico, flying squirrels have been identified as possible vectors of Rickettsia prowazekii. Sporadic cases of epidemic typhus and BZD are reported in these areas and are generally ascribed to contact with these animals. There is no correlation between poverty and zoonotic infection with the causative agent of BZD in these cases.

Clinical presentation of BZD resembles that of epidemic typhus, but the disease follows a milder course. Commonly observed symptoms are malaise, fatigue, fever, chills, headaches, muscle and joint pain as well as rash. If the central nervous system or internal organs are affected, additional complaints may be experienced.

Treatment consists in administration of doxycycline, a tetracycline antibiotic, for up to two weeks. This therapy is very effective, but alternative therapeutic approaches may be necessary in case of pediatric patients or pregnant women. Here, a single-dose therapy is recommended.

1. Raoult D, Woodward T, Dumler JS. The history of epidemic typhus. Infect Dis Clin North Am. 2004; 18(1):127-140.
2. Bechah Y, El Karkouri K, Mediannikov O, et al. Genomic, proteomic, and transcriptomic analysis of virulent and avirulent Rickettsia prowazekii reveals its adaptive mutation capabilities. Genome Res. 2010; 20(5):655-663.
3. Robinson D, Leo N, Prociv P, Barker SC. Potential role of head lice, Pediculus humanus capitis, as vectors of Rickettsia prowazekii. Parasitol Res. 2003; 90(3):209-211.
4. McQuiston JH, Knights EB, Demartino PJ, et al. Brill-Zinsser disease in a patient following infection with sylvatic epidemic typhus associated with flying squirrels. Clin Infect Dis. 2010; 51(6):712-715.
5. Chapman AS, Swerdlow DL, Dato VM, et al. Cluster of sylvatic epidemic typhus cases associated with flying squirrels, 2004-2006. Emerg Infect Dis. 2009; 15(7):1005-1011.
6. Labruna MB. Ecology of rickettsia in South America. Ann N Y Acad Sci. 2009; 1166:156-166.
7. Faucher JF, Socolovschi C, Aubry C, et al. Brill-Zinsser disease in Moroccan man, France, 2011. Emerg Infect Dis. 2012; 18(1):171-172.
8. Bechah Y, Capo C, Raoult D, Mege JL. Infection of endothelial cells with virulent Rickettsia prowazekii increases the transmigration of leukocytes. J Infect Dis. 2008; 197(1):142-147.
9. Bechah Y, Paddock CD, Capo C, Mege JL, Raoult D. Adipose tissue serves as a reservoir for recrudescent Rickettsia prowazekii infection in a mouse model. PLoS One. 2010; 5(1):e8547.
10. Turcinov D, Kuzman I, Puljiz I. [The Brill-Zinsser disease still occurs in Croatia: retrospective analysis of 25 hospitalized patients]. Lijec Vjesn. 2002; 124(10):293-296.
11. Portnoy J, Mendelson J, Clecner B. Brill-Zinsser disease: report of a case in Canada. Can Med Assoc J. 1974; 111(2):166.
12. Cowan G. Rickettsial diseases: the typhus group of fevers--a review. Postgrad Med J. 2000; 76(895):269-272.
13. Svraka S, Rolain JM, Bechah Y, Gatabazi J, Raoult D. Rickettsia prowazekii and real-time polymerase chain reaction. Emerg Infect Dis. 2006; 12(3):428-432.
14. Bise G, Coninx R. Epidemic typhus in a prison in Burundi. Trans R Soc Trop Med Hyg. 1997; 91(2):133-134.
15. Turcinov D, Kuzman I, Herendic B. Failure of azithromycin in treatment of Brill-Zinsser disease. Antimicrob Agents Chemother. 2000; 44(6):1737-1738.