Brill-Zinsser disease is caused by latent infection with Rickettsia prowazekii and reactivation of that pathogen in patients who suffered from epidemic typhus years ago.
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  . 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 :
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  or - in more recent cases - upon previous contact with flying squirrels . 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 , 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 .
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 .
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.
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 .
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 .
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 . 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:
People may import R. prowazekii into previously unaffected regions, as has recently been reported in France . 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 .
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 . 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.
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 . 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.