INTRODUCTION — Bartonella quintana is a species of Bartonella, which historically caused "trench fever", but more recently has been associated with a variety of infections including bacteremia, endocarditis, and bacillary angiomatosis.
The clinical features, diagnosis, and treatment of B. quintana infection will be reviewed here. Endocarditis due to Bartonella spp, Bartonella infection in HIV-infected patients, bacillary angiomatosis, and bartonellosis (or Carrion's disease) are discussed separately. (See "Endocarditis caused by Bartonella" and "Bartonella infections in people with HIV" and "South American bartonellosis: Oroya fever and verruga peruana".)
EPIDEMIOLOGY — B. quintana is a small, fastidious, gram-negative rod formerly known as Rochalimaea quintana, Rickettsia quintana, Rickettsia weigli, Rickettsia volhynia, and Rickettsia pediculi [1].
Early in the 20th century, B. quintana infection emerged as a major source of morbidity and mortality among soldiers and was commonly known as trench fever. During World War I, more than a million soldiers developed trench fever, and military physicians reported on the wide range of clinical manifestations [2,3].
The military physicians established the War Office Trench Fever Investigation Commission and this group identified the human body louse Pediculus humanus variety corporis as the vector for the infectious pathogen, with transmission occurring via inoculation of infected louse feces into abraded skin or conjunctivae [3]. During World War II, a significant, but less extensive, trench fever epidemic occurred. Subsequently, endemic and sporadic outbreaks of trench fever occurred in the middle part of the century in multiple regions of the world, including Ethiopia (1946), Poland (1949), Mexico (1954), USSR (1960), and Tunisia (1961) [4].
Since the 1990s, sporadic B. quintana infections have reemerged in the United States and Europe, most often manifesting as bacteremia [5,6], endocarditis [7-10], or bacillary angiomatosis [11,12]. Contemporary B. quintana infections have disproportionately affected homeless persons, especially those with chronic alcoholism [5-7,13]. One study from France noted intraerythrocytic organisms in a small proportion of erythrocytes from 9 of 18 homeless individuals with B. quintana bacteremia; the authors speculated that infection of erythrocytes could allow body lice to efficiently transmit B. quintana [14].
Although investigators have reported scattered outbreaks of contemporary B. quintana infections, serologic studies suggest that exposure to the pathogen among certain at-risk populations is more common than overt clinical disease. In studies of impoverished or homeless populations in the United States and France, B. quintana antibodies were present in 8 to 53 percent compared with 0 to 2 percent of healthy blood donors [15-19]. The frequency of current infection, as determined by blood culture, was assessed in a report of 930 homeless patients and 217 sex-and age-matched controls: B. quintana was isolated in 5.3 and 0 percent, respectively [18].
Transmission — Lice generally have been considered to be the major vector for B. quintana in classic trench fever [1,3]. Although three lice species, Pediculus humanus var capitis (head louse), P. humanus var corporis (body louse), and P. humanus var pubis (pubic louse), can potentially transmit B. quintana, available data suggest the body louse is the predominant vector. Since B. quintana propagates in the intestinal lumen of the body louse, not in the intestinal epithelial cells [20], infection probably results from contact with contaminated louse feces. One study from 1939 documented the presence of B. quintana in ticks that had fed on humans who had a trench fever-like illness [21].
Most experts also believe that lice serve as the source of contemporary B. quintana infections:
●In one study, B. quintana infection occurred among a cluster of homeless persons with HIV infection, most of whom had head or body lice exposure [11].
●In another series from Russia, 33 (12.3 percent) of 268 body lice samples from homeless men were positive for B. quintana using polymerase chain reaction (PCR) testing [22]. The same investigators found a similar prevalence of B. quintana-infected lice in Burundi [22,23].
●The most convincing evidence implicating lice in contemporary B. quintana infections was the isolation of the organism from lice extracted from three patients with B. quintana bacteremia in Marseilles, France [6].
●In San Francisco, investigators used PCR techniques to identify B. quintana in lice pools from homeless persons infested with head or body lice [24]. They identified B. quintana in 33 percent of pooled samples of body lice and in 25 percent of pooled head lice samples.
●B. quintana could be cultured from 15 of 161 body lice obtained from homeless persons in Marseilles; PCR-based tests detected B. quintana in 41 of these 161 body lice [25].
●In an experimental model, investigators provided a blood meal containing B. quintana to body lice and then analyzed the bacterial replication [26]. B. quintana became detectable in the lice within four days, and the lice had continued excretion of B. quintana in the feces for at least three weeks. On day 15, the lice were excreting millions of B. quintana per day.
Rarely, exposure to cats or their fleas may be associated with the transmission of B. quintana, in contrast to Bartonella henselae infection, which generally results from cat exposures. As an example, during an outbreak of B. quintana in Seattle, three patients reported a recent cat scratch [5]; in a separate case report, a cat owner developed bacteremia and lymphadenopathy due to B. quintana [27]. Although cats are not a natural host for B. quintana [28], B. quintana has been isolated from cat dental pulp and cat fleas [1]. In vitro experimental models have also established that cat fleas can acquire B. quintana through feeding, and then excrete the organisms in their feces [29]. One study also found that bed bugs (Cimex lectularius) can acquire B. quintana and release the bacteria in their feces [30]. The biologic role for fleas or bed bugs in the transmission of B. quintana to humans remains unknown [29,30].
Humans are considered the main host for B. quintana. In both classic and contemporary trench fever, B. quintana occurs in situations that foster very close contact of humans, particularly those with poor hygienic practices. Several reports have also documented isolation of B. quintana in macaques, and prior inoculation studies found chronic B. quintana bacteremia could be established in macaques. In addition, in a study involving primate centers in China, B. quintana was detected in blood of more than 10 percent of the macaques, and the genetic diversity of B. quintana in the macaques was much broader than observed in humans [31]. These findings suggest non-human primates serve as a natural host for B. quintana and that subsets of B. quintana strains in macaques may have spilled over into human populations [31]. Thus, B. quintana disease in humans may have a zoonotic origin.
CLINICAL MANIFESTATIONS — Infection with B. quintana can lead to an array of clinical presentations that generally depend upon the immune status of the infected individual [32].
Classic trench fever — Classic trench fever includes a variety of clinical manifestations, ranging from a mild influenza-like illness to a moderately severe, chronic, debilitating disease [2,21,33]. Most persons who develop these symptoms presumably have bacteremia with B. quintana. Clinical observations from persons infected during World War I suggested an average incubation period of 7.7 days [3]. Data from controlled studies in human volunteers inoculated with B. quintana-infected louse feces indicate an incubation range of 5 to 20 days [33].
The symptoms and signs of the acute disease typically include malaise, fever, headache, dizziness, bone pain (particularly of the shins), splenomegaly, nausea, vomiting, and, in some instances, a macular truncal rash [3]. Investigators have observed four major fever patterns associated with classic trench fever [2,33]:
●An isolated febrile episode
●A single febrile episode lasting four to five days
●Three to five recurrent febrile episodes, each lasting four to five days and punctuated by asymptomatic intervals also four to five days in duration
●Persistent fever lasting two to six weeks
The term "quintan fever" derives from the recurring five day attacks. Among the four fever patterns, the episodic pattern occurs the most frequently. In some instances, patients may develop persistent bacteremia without fever. The primary clinical episode can be followed by prolonged bacteremia lasting weeks to months. Death rarely occurs in either the acute or chronic illness [2,33].
Contemporary B. quintana infections — Contemporary B. quintana infections were first described in individuals with HIV in the early 1990s [12,34]. In a study of 46 persons with HIV infection, B. quintana predominantly caused bacillary angiomatosis, manifesting as cutaneous lesions, subcutaneous masses, or bone lesions, but not lymph node, liver, or splenic lesions (as commonly seen with B. henselae infection) [11]. (See "Bartonella infections in people with HIV".)
The clinical manifestations of contemporary B. quintana infections among immunocompetent persons have differed from those in patients with HIV and have more closely resembled classic trench fever. Among the 10 patients involved in the cluster of B. quintana bacteremia from a 1993 Seattle outbreak, seven had a temperature greater than 38.5°C and one had hypothermia (median temperature 38.5°C) [5]. Three had weight loss that exceeded 20 pounds (9.1 kg), and two had splenomegaly. Six of the 10 patients had three or more blood cultures positive for B. quintana, and 4 of 10 had positive blood cultures separated by at least 10 days.
In the 1997 study in Marseilles, France, B. quintana bacteremia occurred in 10 (14 percent) of 71 homeless persons evaluated at an emergency department [6]. Most of those patients with B. quintana bacteremia had an illness characterized by leg pain, headaches, and thrombocytopenia; only one had the typical shin pain described with classic trench fever. Two of 10 patients had a temperature greater than 38°C, and several of the patients had chronic bacteremia with few or no symptoms.
In the Seattle outbreak, 2 of the 10 patients had endocarditis. Similarly, in a report from France, three patients with B. quintana bacteremia developed endocarditis [7]. In a subsequent multicenter international study from France, England, Canada, and South Africa, investigators evaluated patients with blood culture-negative endocarditis and found 22 patients with Bartonella endocarditis, including five with B. quintana infection [8]. (See "Endocarditis caused by Bartonella".)
Although contemporary B. quintana infections have not generally been associated with lymphadenopathy, there are several case reports of patients with B. quintana bacteremia and adenopathy. One 30-year-old woman developed cervical adenopathy [27], and a hemodialysis patient had generalized lymphadenopathy [35].
DIAGNOSIS — The diagnosis of B. quintana infection is challenging. A definitive diagnosis of Bartonella infection is made by isolating the organism from a culture of blood or tissue. However, because Bartonella is so difficult to isolate in culture, the diagnosis is more often made based on supportive diagnostic tests, such as serology and polymerase chain reaction testing. In general, Bartonella serologic testing should not stand alone as a means to diagnose Bartonella infection and should be interpreted in the context of the epidemiologic features and clinical manifestations. Histopathology does not typically play an important role in the diagnosis of B. quintana infections, except in persons with HIV who have cutaneous bacillary angiomatosis.
Culture — B. quintana is a fastidious gram-negative bacterium that requires specific laboratory conditions to enhance the yield of culture. Preferably, blood culture samples should be incubated in pediatric or adult isolator tubes or by using EDTA blood tubes. In some instances, Bartonella species have been isolated from BACTEC bottles.
It is important to proactively communicate with the microbiology laboratory that Bartonella is a potential diagnosis so that the laboratory can optimize culture techniques and can extend the incubation period for a minimum of 21 days. Isolation of organisms from subcultures is enhanced by plating samples onto either chocolate agar or heart infusion agar supplemented with 5 percent rabbit blood. Optimally, the microbiology lab should use fresh agar plates and incubate them in 5 percent CO2 at 35 to 37°C for a minimum of 21 days (incubation periods as long as 45 days have been documented). Identifying B. quintana within erythrocytes has led one group to recommend freezing blood samples prior to plating to release intracellular bacteria and thus enhance the yield of blood culture samples [14].
Histopathology — Standard histologic hematoxylin and eosin staining of bacillary angiomatosis lesions from any site characteristically shows lobular vascular proliferations composed of rounded vessels lined by variably protuberant plump endothelial cells [36]. Clusters of neutrophils, neutrophilic debris, and lymphocytes are also scattered throughout the lesions, especially around eosinophilic granular aggregates. Warthin-Starry silver staining of these aggregates reveals masses of small, dark-staining bacteria. Electron microscopic examination, if performed, shows pleomorphic bacilli with a trilaminar wall [37].
Serology — Antibody production in response to B. quintana infection appears to be variable. As an example, patients with acute trench fever typically develop significant titers of anti-Bartonella antibody, whereas those with chronic B. quintana bacteremia often have minimal anti-Bartonella antibody response [6]. When individuals recover from chronic infection, they typically generate detectable, but low antibody titers. In contrast, persons with endocarditis due to this organism often have high antibody titers [7].
Two serologic methods, indirect fluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA), are available for the diagnosis of B. quintana infections. These serologic tests generally distinguish Bartonella from other genuses of bacteria.
Problems with the B. quintana IFA serology tests include:
●Significant cross reactivity occurs at the species level between B. quintana and B. henselae, especially for IgG assays.
●The sensitivity of the test does not appear to be optimal, especially with IgG assays.
●The prevalence of positive Bartonella serology in the general population is 4 to 6 percent, which creates difficulties with false positive tests.
Although both the IFA and EIA serologic tests have undergone study, most commercially available assays use the IFA test.
In general, IFA IgG titers <1:64 suggest the patient does not have a current Bartonella infection. Titers <1:64 could represent past infection. Titers >1:64 but <1:256 represents possible Bartonella infection and repeat testing in 10 to 14 days is generally recommended. Titers >1:256 strongly suggest active or recent infection.
Polymerase chain reaction — Qualitative polymerase chain reaction (PCR)-based tests play an important role in the diagnosis of Bartonella-associated infections because of the difficulty in culturing Bartonella species from blood and tissue samples [38,39]. Multiple commercial laboratories now offer PCR testing, including Real-Time PCR, but only some differentiate B. quintana from B. henselae. For patients with suspected bacteremia, Bartonella PCR testing can be performed on whole blood, plasma, or serum samples.
THERAPY — The choice of antibiotic therapy for B. quintana infection is problematic for a number of reasons:
●Data on the efficacy of treatment are sparse.
●In vitro data have not correlated well with clinical responses, especially since B. quintana resides within cells and has some protection from host defenses [40].
●A true clinical response to antibiotics may be difficult to judge since some patients with B. quintana bacteremia have minimal or no clinical symptoms.
●Long-term follow-up of treated patients has been limited, making it difficult to judge treatment responses [5].
The efficacy of antibiotic therapy was directly addressed in a randomized trial involving homeless patients with B. quintana bacteremia who were assigned to either no treatment or a combination of 28 days of oral doxycycline plus 14 days of intravenous gentamicin [41]. Using intention-to-treat analysis, bacteremia was eradicated significantly more often with antibiotic therapy (7 of 9 versus 2 of 11). Among those who completed the protocol, eradication of B. quintana occurred in all seven treated patients compared with only two of nine untreated patients.
A benefit from aminoglycoside therapy was also suggested in a retrospective analysis of 101 patients with endocarditis [42]. Patients who received a regimen that included at least 14 days of an aminoglycoside had a greater likelihood of achieving full recovery and surviving the infection than those treated only with doxycycline. (See "Endocarditis caused by Bartonella".)
Optimal therapy of B. quintana infection is uncertain given the limited published treatment data, and, inadequate data exist to guide the duration of therapy. The following recommendations are separated by the clinical presentation and are based on available data [40] and expert panel guidelines [43].
●For patients who have acute or chronic B. quintana bacteremia without endocarditis, expert guidelines recommend doxycycline 200 mg orally once daily for four weeks plus gentamicin 3 mg/kg IV once daily for the first two weeks [43]. Doxycycline 100 mg orally twice daily is reasonable as an alternative to doxycycline 200 mg once daily. If gentamicin cannot be used, then it should be replaced with rifampin 300 mg orally twice daily for two weeks.
●Patients with chronic B. quintana bacteremia should undergo careful evaluation for endocarditis, since endocarditis requires a longer duration of antimicrobial therapy and closer monitoring and long-term follow-up. The treatment of endocarditis caused by B. quintana is discussed separately. (See "Endocarditis caused by Bartonella".)
●The treatment of B. quintana in persons with HIV who have bacillary angiomatosis is discussed separately. (See "Microbiologic diagnosis of Bartonella infections" and "Bartonella infections in people with HIV".)
●Trimethoprim-sulfamethoxazole, fluoroquinolones, penicillins, and first-generation cephalosporins probably do not have reliable activity against B. quintana and thus are not recommended.
SUMMARY AND RECOMMENDATIONS
●Bartonella quintana is a small, fastidious, gram-negative rod that belongs to the species of Bartonella. B quintana historically caused "trench fever," but in modern times, it has been associated with a variety of infections, including bacteremia, endocarditis, and bacillary angiomatosis. (See 'Introduction' above.)
●Since the 1990s, sporadic B. quintana infections have reemerged in the United States and Europe and contemporary B. quintana infections have disproportionately affected impoverished and homeless persons, especially those with chronic alcoholism. (See 'Epidemiology' above.)
●Although investigators have reported scattered outbreaks of contemporary B. quintana infections, serologic studies suggest that exposure to B. quintana with subclinical infection among certain at-risk populations is more common than overt clinical disease. (See 'Epidemiology' above.)
●Lice generally have been considered to be the major vector for B. quintana in classic trench fever. Available data suggest that the body louse is the predominant vector and infection probably results from contact with contaminated louse feces. Humans are the only known host for this organism. (See 'Transmission' above.)
●In both classic and contemporary trench fever, B. quintana occurs in situations that foster very close contact of humans, particularly those with poor hygienic practices. (See 'Transmission' above.)
●Infection with B. quintana can lead to an array of clinical presentations that generally depend upon the immune status of the infected individual:
•Classic trench fever includes a variety of clinical manifestations, ranging from a mild influenza-like illness to a moderately severe, chronic, debilitating disease. Most persons who develop these symptoms presumably have bacteremia with B. quintana. The symptoms and signs of the acute disease typically include malaise, fever, headache, bone pain (particularly of the shins), splenomegaly, and, in some instances, a maculopapular rash. (See 'Classic trench fever' above.)
•Contemporary B. quintana infections were first described in individuals with HIV infection in the early 1990s. In such patients, B. quintana predominantly caused bacillary angiomatosis, manifesting as cutaneous lesions, subcutaneous masses, or bone lesions, but not lymph node, liver, or splenic lesions (as commonly seen with Bartonella henselae infection). (See 'Contemporary B. quintana infections' above.)
•The clinical manifestations of contemporary B. quintana infections among immunocompetent persons have differed from those with HIV and have more closely resembled classic trench fever. Most immunocompetent persons with B. quintana infection have had bacteremia, and some have had endocarditis. (See 'Contemporary B. quintana infections' above.)
●A definitive diagnosis of Bartonella infection is made by isolating the organism from a culture of blood or tissue. More frequently, the diagnosis is made based on epidemiologic features and clinical manifestations combined with supportive diagnostic tests, such as serology or polymerase chain reaction. Histopathology does not typically play an important role in the diagnosis of B. quintana infections, except in persons with HIV infection who have cutaneous bacillary angiomatosis. B. quintana is a fastidious gram-negative bacterium that requires specific laboratory conditions to enhance the yield of culture. (See 'Diagnosis' above.)
●Definitive antibiotic therapy recommendations for B. quintana infection are problematic because of limited treatment efficacy data, relatively poor correlations of in vitro data and clinical responses, and difficultly judging treatment response in the subset of patients with B. quintana bacteremia who have minimal or no clinical symptoms. (See 'Therapy' above.)
●For patients who have acute or chronic B. quintana bacteremia without endocarditis, we administer doxycycline 200 mg orally once daily (or 100 mg twice daily) for four weeks plus gentamicin 3 mg/kg IV once daily for the first two weeks. If gentamicin cannot be used, then it should be replaced with rifampin 300 mg orally twice daily for two weeks. (See 'Therapy' above.)
●Patients with chronic B. quintana bacteremia should undergo careful evaluation for endocarditis, since endocarditis requires a longer duration of antimicrobial therapy and closer monitoring and long-term follow-up. The treatment of endocarditis caused by B. quintana is discussed separately. (See "Endocarditis caused by Bartonella".)
●The treatment of B. quintana in persons with HIV infection and bacillary angiomatosis is discussed separately. (See "Microbiologic diagnosis of Bartonella infections" and "Bartonella infections in people with HIV".)
