Trench fever is a clinical syndrome caused by infection with Bartonella quintana; the condition was first described during World War I. Contemporary B quintana disease, commonly referred to as urban trench fever, is typically found in homeless, alcoholic, and poor populations.
The human body louse Pediculus humanus var corporis is the major vector involved in trench fever transmission[1, 2] (see the image below).
View Image | Dorsal view of female body louse, Pediculus humanus var corporis. This louse is a known vector responsible for transmission of epidemic typhus, trench.... |
Classic symptoms of trench fever include the following:
Urban trench fever typically includes 1 or more of these symptoms, but the presentation tends to be more variable.
Three additional syndromes are associated with B quintana infection, as follows:
Characteristics of classic trench fever were fairly consistent, as follows:
Physical findings of urban trench fever are more variable, but tend to include the following:
Common findings in associated syndromes of urban trench fever are as follows:
Many patients with microbiologic or serologic evidence of B quintana infection are asymptomatic.
See Presentation for more details.
B quintana infection is difficult to diagnose in the laboratory. The following studies may be useful:
See Workup for more details.
Current antibiotic recommendations for each of the identified clinical syndromes associated with B quintana in immunocompetent patients are as follows:
Surgical biopsy may help diagnose B quintana endocarditis, lymphadenopathy, or bacillary angiomatosis. Valve replacement surgery is required in most cases of B quintana endocarditis.
See Treatment and Medication for more details.
Trench fever is a clinical syndrome caused by infection with Bartonella quintana. The condition was first described during World War I, when it affected nearly 1 million soldiers.[3, 4, 1, 2] It has been known by several different names, including quintan fever, 5-day fever, shin bone fever, tibialgic fever, Wolhynia fever, and His-Werner disease.
DNA studies have demonstrated that many soldiers in Napoleon’s Grand Army at Vilnius in the 19th century were infected with B quintana. In addition, B quintana DNA was found in a 4000-year-old human tooth in Roaix, France.[5, 6] Reports of trench fever outbreaks stopped after World War I and then reappeared transiently on the Eastern Front in Europe during World War II.
By the end of World War I, the human body louse Pediculus humanus was recognized as the likely vector for trench fever transmission.[1, 2] Rickettsia -like organisms in the body and feces of P humanus were postulated to be the cause. In 1969, Vinson et al successfully cultivated the causative organism (then called Rickettsia quintana) from a sick patient and reproduced the disease by inoculating healthy volunteers.[7] The organism was briefly placed in the genus Rochalimaea before being reclassified as Bartonella quintana in 1993.
During World War I, trench fever was characterized by the abrupt onset of fever, malaise, myalgias, headache, transient macular rashes of the torso, pain in the long bones of the leg (shins), and splenomegaly.[8, 9, 1, 2, 3, 4, 10, 11] Typical periodic cycles of fever, chills, and sweats occurred at 5-day intervals, resulting in prolonged disability lasting 3 months or longer in young soldiers. However, no deaths attributable to trench fever have ever been reported.
Over the past 3 decades, Bartonella species have emerged as a cause of bacteremia, angioproliferative disease (eg, bacillary angiomatosis), and endocarditis in patients with and without HIV infection. In 1995, B quintana was found to cause bacteremia in 10 homeless, HIV-negative alcoholics.[12] In 1999, B quintana endocarditis was described in 3 HIV-negative homeless alcoholic men.[13] These cases suggest that B quintana disease is not limited to wartime outbreaks or immunocompromised persons.
Subsequently, sporadic cases and small clusters of B quintana infection have been described worldwide and appear to be associated with poor sanitation, poor hygiene, alcoholism, and malnutrition—all of which are commonly seen in both classic and urban trench fever cases. Seroprevalence studies suggest that B quintana infection is more common than is clinically recognized and that many infections are subclinical.
The term urban trench fever is applied to contemporary B quintana disease. Urban trench fever is typically found in homeless, alcoholic, and poverty-stricken populations, among whom poor personal hygiene is common. The infection affects both immunocompetent and immunocompromised persons. Some (but not all) persons with urban trench fever have evidence of louse infestation.
The spectrum of disease associated with B quintana infection includes asymptomatic infection, urban trench fever, angioproliferative disease, chronic lymphadenopathy, bacteremia, and endocarditis.[9, 14, 15]
The human body louse P humanus var corporis is the major vector involved in trench fever transmission (see the image below).[1, 2]
View Image | Dorsal view of female body louse, Pediculus humanus var corporis. This louse is a known vector responsible for transmission of epidemic typhus, trench.... |
After B quintana is introduced into the human body, it invades erythrocytes and endothelial cells, where it is protected from the host’s humoral immune response.[16] Intraerythrocytic B quintana colonization is largely limited to human beings,[9, 14] while the invasion of vascular endothelial cells is less species-specific.[17] Monocytes from homeless individuals with chronic B quintana bacteremia have been shown to overproduce interleukin (IL)–10, resulting in an attenuated immune response that may facilitate the bacterial persistence.[18] These same patients generate a poorer humoral response than patients with endocarditis, in whom the inflammatory response is more dramatic and bacteremia less frequent.[19]
Once the organism invades and begins to multiply within endothelial cells, proinflammatory cytokines are activated, apoptosis suppressed, and vascular proliferation initiated.[20] These changes result in systemic symptoms, bacteremia, endovascular infection, and lymphatic enlargement. The relationship between the endothelial vascular proliferation and the destructive valvular lesions of B quintana endocarditis is unknown. A potential connection might be the presence of variably expressed outer-membrane proteins in some strains of B quintana. These proteins induce secretion of vascular endothelial growth factor and are associated with increased rates of invasion.[21]
Despite this possible immunologic association, the histologic features of these two clinical variants differ.[9] The pathogenesis of B quintana –associated disease suggests that bacteremia is an early occurrence common to all of the various syndromes attributed to it. In some patients, the bacteremia lasts for a few days, whereas, in others, it lasts for months to years.[14]
B quintana causes both trench fever and urban trench fever.[9, 7] Humans are the predominant reservoir of the pathogen, although infection has been documented in some nonhuman primates and in cats.[22, 23, 24, 25] In infected persons, the organisms can be found in human blood, tissues (particularly skin), and urine.[9]
B quintana bacteremia may be intermittent or prolonged for years, suggesting that blood-sucking arthropods are efficient transmitters of B quintana infection.[16, 14] External parasitic infestations are also associated with conditions of squalor. Although the body louse P humanus is the major vector for both trench fever and urban trench fever, its presence is not always demonstrated in patients with urban trench fever.[7, 13, 26]
Breaks in the skin contaminated by louse feces and arthropod bites are documented portals of entry. Other possible vectors include mites, ticks, and fleas.[9] A 2014 study showed that cat fleas (Ctenocephalides felis) can ingest B quintana and release viable bacteria into their feces.[27] Contamination of mucous membranes, transfusion, transplantation, and IV drug abuse are also potential avenues of entry. Human-to-human transmission of trench fever has not been described.
Predisposing factors for B quintana infection include war, famine, malnutrition, homelessness, alcoholism, intravenous (IV) drug abuse, and poor hygiene.
B quintana was found in the lice of 33.3% of body lice–infested and 25% of head lice–infested homeless persons in California.[28] In one study, 20% of the patients in a downtown Seattle clinic that serves a homeless indigent population had microimmunofluorescent antibody titers of 1:64 or greater to Bartonella species.[29] Multivariate analysis of these patients revealed that alcohol abuse was the only independent variable associated with seropositivity. It is difficult, however, to ascertain the true incidence of urban trench fever, as most infected individuals are asymptomatic. Moreover, the disease occurs sporadically and in small clusters of homeless persons.
B quintana –related illness has been found on every continent except Antarctica. Well-performed seroprevalence studies have identified patients with B quintana antibodies in France, Greece, Sweden, Japan, Brazil, Croatia, and Peru.[19, 30, 31, 32, 33, 34, 35] Cases of culture-negative endocarditis with antibody titers positive for B quintana have been reported in Europe, Australia, Japan, Tunisia, and India.[36, 37, 38, 39, 40]
Whereas trench fever described during wartime typically affected young soldiers, urban trench fever typically affects middle-aged adults. Rare cases of Bartonella endocarditis and central nervous system (CNS) infection have been described in children.
Because trench fever was historically an infection of soldiers, most of the cases documented during World Wars I and II were in males. Cases of urban trench fever described since 1995 have also predominantly involved males, reflecting the disproportionate representation of males in the homeless alcoholic population.
No convincing data suggest that urban trench fever or other syndromes caused by B quintana infection have a racial or ethnic predilection.
In most immunocompetent hosts, B quintana infection is self-limited unless endocarditis occurs. In immunocompromised hosts, however, B quintana infection tends to be more severe and may result in death.
During World War I, trench fever resulted in significant morbidity and prolonged disability but no recognized mortality. Contemporary descriptions of B quintana endocarditis in homeless alcoholic males have found mortality rate to be as high as 12%, with most deaths related to complications of endocarditis or to the surgery used in its treatment.[41, 42]
Patients should be educated about practicing good personal hygiene and improving their living conditions. Vector control of the body louse should also be explained.
During World War I, trench fever was recognized and precisely described as a distinct syndrome by several physicians.[8, 3, 4, 1, 2] The clinical incubation period was 3-48 days.[23] Associated lice infestation was common. Young soldiers with trench fever would experience headache, relapsing fevers, shin pain, truncal rash, and splenomegaly. Most patients could vividly remember the specific time of symptom onset.
The differential diagnoses of the initial symptoms associated with trench fever included typhoid fever, epidemic typhus, influenza, and meningitis. Although there was no recognized mortality, it caused serious and prolonged disability.
Headaches were sudden in onset and were described as frontal or retro-orbital. They were often associated with a stiff neck and photophobia, raising the possibility of meningitis. Other neuropsychiatric symptoms included weakness, depression, restlessness, and insomnia. Many patients with trench fever would experience severe prostration.
The dramatic onset of fever coincided with the onset of headaches. Temperatures were often as high as 104°F and were associated with malaise, chills, and sweats. Fever occurred in one of 3 distinct patterns, as follows:
Bone pain, particularly involving the shins, progressively worsened throughout the duration of illness. The pain became dramatically worse with exercise and could be so severe that it prevented patients from even changing position in bed. Another common site of pain was the loin with radiation to the lower extremities or into the upper back.
Gastrointestinal (GI) symptoms of trench fever would begin with diffuse abdominal pain, often associated with anorexia, nausea, vomiting, weight loss, diarrhea, and constipation.
Conjunctivitis was another common initial symptom. An erythematous truncal rash and tachycardia would develop during the febrile episodes. Dyspnea could also be present.
Urban trench fever has been characterized by one or more of the symptoms described above, but the presentation tends to be more variable.[9, 43, 36, 12, 14, 41] Urban trench fever occurs in homeless and alcoholic persons who exhibit poor personal hygiene. The presence of lice and other external parasites is less prevalent in these individuals. Headaches, conjunctivitis, relapsing fever, and shin pain have been documented, whereas abdominal and neurologic symptoms appear to be uncommon.
The descriptions of other syndromes associated with B quintana infection over the past 30 years were unknown to physicians during World War I. A large percentage of persons with B quintana infection may be asymptomatic, and those with syndromes consistent with infection may have negative blood culture results. Typical manifestations of these associated syndromes are as follows:
Chronic B quintana bacteremia is occasionally accompanied by all of the syndromes described above and may last for years.[19]
The physical findings of trench fever during World War I were fairly consistent. Infected persons experienced an abrupt onset of fever (up to 104°F), associated with chills and diaphoresis. Patients would initially exhibit a toxic appearance associated with prostration. A furred or coated tongue was common. Some patients were able to continue with their daily activities and recover after a short fastigium, but most would develop a significant disability for months.
Patients with trench fever exhibited a characteristic nonpruritic, blanching, erythematous, macular rash that typically started on the trunk and extended as far as the abdomen, neck, and proximal extremities. The rash accompanied the fever, recurring with each febrile paroxysm. Although the rash was not pruritic, coexisting body louse and scabies infestations caused pruritus and excoriations.
The vast majority of patients with trench fever developed conjunctivitis at the onset of illness. Photophobia was common. Paroxysmal tachycardia generally paralleled the fever. Splenomegaly was common in those with more prolonged courses of illness. Bone and muscle tenderness accompanied the shin pain and became progressively more severe and debilitating as the disease progressed. Loss of the Achilles reflex, a manifestation of peripheral neuropathy, was common.
The physical findings of urban trench fever are more variable. Rash, fever, conjunctivitis, bone tenderness, splenomegaly, and neurologic signs (eg, absent Achilles reflexes) have been documented but are generally less prevalent than in the case descriptions from World War I. Nonspecific findings such as weight loss and weakness have been reported. Lastly, many patients with microbiologic or serologic evidence of B quintana infection are asymptomatic.
Patients with chronic lymphadenopathy usually have lymphatic involvement of the cervical and mediastinal lymph nodes. They do not experience fever and are otherwise asymptomatic.
Bacillary angiomatosis typically presents with one or more papules that progress to nodules and may be confined to one or more anatomic regions. In immunocompromised patients, however, lesions tend to be more widespread and are more likely to involve viscera such as the liver, spleen, and GI tract. The lesions are red, purple, or nonpigmented and can be superficial or subcutaneous. They may be mobile or fixed to underlying structures (eg, bone). Regardless of appearance, they bleed profusely when punctured or incised. Associated regional adenopathy is common.
Immunocompetent patients with bacillary angiomatosis are typically afebrile. The same lesions occurring in immunocompromised patients are generally more widespread and are more likely to involve visceral organs such as the liver, spleen, and GI tract.
Patients with B quintana endocarditis present with fever and murmur. Lesions typically involve the left-sided heart valves, resulting in mitral insufficiency, aortic insufficiency, or both. Right-sided cardiac involvement is unusual. Heart failure may occur, and embolic lesions develop in as many as 20% of patients.[42]
Interestingly, Koo et al implicated B Quintana in a culture-negative mycotic abdominal aortic aneurysm in a patient with chronic back pain but without other signs of infection. The diagnosis was made by polymerase chain reaction (PCR) and mass spectrometry of tissue sample.[44]
B quintana infection is difficult to diagnose in the laboratory. Therefore, the microbiology laboratory must be consulted to maximize the diagnostic yield.
Blood cultures have poor sensitivity for detecting B quintana. Serologic testing is also unhelpful because of poor specificity resulting from frequent cross-reactivity with other organisms, and testing is further hampered by inadequate immune responses in immunocompromised individuals.
PCR-based genomic testing is sensitive and specific but is technically demanding. Therefore, the microbiology laboratory must be consulted to maximize the diagnostic effort.
Transthoracic and/or transesophageal echocardiography can identify the presence of valvular vegetations in cases of Bartonella endocarditis.
Blood cultures obtained for the diagnosis of Bartonella infection are typically low-yield procedures in most laboratories. The Clinical Laboratory Standards Institute notes that lysis-centrifugation techniques in combination with inoculation of fresh enriched chocolate agar are optimal.[45] The plates should be incubated at 35°C in a humid, carbon dioxide–rich environment for 14-21 days.
Newer broth lytic systems can be used for a 7-day incubation period, followed by subculture onto enriched chocolate media in a humid, carbon dioxide–rich environment at 35°C for 21 days. An older protocol using BACTEC blood culture bottles involves staining with acridine orange after 7 days of incubation.[46] If organisms are seen, blood or chocolate subcultures are incubated at 37°C in a humid, carbon dioxide–rich environment for up to 4 weeks.
Immunofluorescent assays (IFAs) for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibody levels for both B quintana and B henselae are available in most reference laboratories and some tertiary care centers. These antibody tests may cross-react and should therefore be quantitated in tandem for comparison to establish a diagnosis.[9] Serologic cross-reactivity between antibodies against B quintana and those against Chlamydia pneumoniae and Coxiella burnetii is common.[9, 47, 36, 33] Acute and convalescent IFA titers for each of these organisms can be diagnostic.
Enzyme immunoassay (EIA) and enzyme-linked immunosorbent assay (ELISA) techniques have been described and are available in some laboratories.
Serologic testing is positive for antibodies (IgG titers >1/50) to B quintana in many patients with trench fever, urban trench fever, Bartonella bacteremia, or angioproliferative disease. Such testing is helpful for diagnosis and seroprevalence studies.[19, 26] The highest levels of antibodies are found in patients with Bartonella endocarditis (IgG titers >1/800).[19] Patients with chronic Bartonella bacteremia have low or absent antibody levels.
Several PCR-based genomic assays and histochemical stains that allow direct detection of Bartonella DNA in both tissue and blood have been developed. These are very specific when results are positive.[9] Detection of B quintana DNA in vegetations from immunocompetent patients is essential in the diagnosis of endocarditis. Bartonella DNA testing via PCR is available at the Centers for Disease Control and Prevention (CDC) and at most reference laboratories.
Biopsy of skin lesions in patients with Bartonella infection shows perivascular lymphocytic infiltrates with some inflammatory cells. Bartonella organisms can be detected in the interstitial tissues. Lesions may also involve liver, spleen, bone marrow, and lymphatic tissues.[9]
The histology of enlarged lymph nodes reveals a noncaseating granulomatous reaction similar to that seen in catscratch disease.[9] Bartonella organisms cannot be demonstrated via light microscopy.
The pathology of involved cardiac valvular tissue reveals a destructive mononuclear inflammatory reaction with focal calcifications.[9] Bartonella organisms can be detected with PCR techniques.
No well-designed, double-blinded, controlled trials have documented the best antibiotic regimen for B quintana infection and its associated syndromes (including trench fever) in immunocompetent patients. Most therapeutic recommendations are based on anecdotal clinical experience.
Pregnancy affects the appropriate choice of antibiotics for treatment. Teratogenic and congenital effects of maternal infection are unknown, as is the impact on pregnancy.
Initial management of severe Bartonella infections, including trench fever and urban trench fever, may require inpatient management. Generally, the consolidation phase of treatment can be provided on an outpatient basis.
An infectious disease specialist may be consulted for help with diagnosis and treatment. A microbiology laboratory may be consulted for help with blood and tissue specimen handling to ensure optimal culture, serologic, and PCR-genomic testing.
In the laboratory, B quintana appears to be sensitive to advanced-generation beta-lactams, chloramphenicol, macrolides, tetracyclines, fluoroquinolones (though not ciprofloxacin), aminoglycosides, rifampin, and trimethoprim-sulfamethoxazole.[14, 48, 49]
Microbiologic susceptibility studies may not accurately predict clinical efficacy, in that B quintana seems to respond clinically to bacteriostatic agents such as doxycycline, erythromycin, and azithromycin.[23] Only gentamicin is bactericidal in vitro.[50] Because gentamicin does not achieve bactericidal levels within human erythrocytes, it is not believed to be optimal for monotherapy, but it is regularly used in combination with doxycycline.
For treatment of serious or complicated infections, it is critical to use combination therapy with two agents known to exhibit good in vitro activity against B quintana.[48] Based on reports of successful treatment in immunocompromised patients, which are mostly anecdotal, longer treatment regimens in conjunction with close clinical and microbiologic follow-up is recommended.
The following are current recommendations for each of the identified clinical syndromes associated with B quintana in immunocompetent patients:
Surgical biopsy may be used when necessary to establish a definitive diagnosis of B quintana endocarditis, lymphadenitis, or bacillary angiomatosis.
In addition to numerous descriptions of small numbers of patients with B quintana endocarditis, 2 large studies (both performed by the same group of investigators) have described the treatment and outcomes of the disease.[41, 42] The findings of these studies suggested that, in most cases of B quintana endocarditis, valvular cardiac surgery is required.
No dietary restrictions are necessary in patients with Bartonella infection, including trench fever and urban trench fever.
No activity restrictions are necessary unless a patient has cardiac failure due to Bartonella endocarditis or its complications. Patients should take steps to improve their hygiene and living conditions. Individuals should avoid donating blood or tissue if they are at risk for Bartonella infection.
B quintana infection can be prevented via avoidance or rapid treatment of lice infestations, as follows:[14, 53, 54]
The goal of antibiotic therapy is to eradicate all forms of B quintana infection, minimizing morbidity and mortality.
Clinical Context: Doxycycline is a synthetically derived broad-spectrum antibiotic in the tetracycline class. It is almost completely absorbed, is concentrated in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations. Doxycycline is bacteriostatic, and its mechanism of action is inhibition of protein synthesis through binding to the 50S subunit of the ribosome. Tetracyclines, as a class, evoke a dramatic response, with rapid disappearance of the associated symptoms and defervescence (usually in 1-2 days).
Clinical Context: Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is bactericidal; it arrests bacterial growth by binding to 1 or more of the penicillin-binding proteins.
Clinical Context: Gentamicin is an aminoglycoside antibiotic used for coverage of gram-negative bacteria, including Pseudomonas species. It is synergistic with beta-lactamase against enterococci. It interferes with bacterial protein synthesis by binding to 30S and 50S ribosomal subunits.
Dosing regimens for gentamicin are numerous and are adjusted on the basis of creatinine clearance and changes in the volume of distribution, as well as the body space into which the agent must distribute. Doses may be given either intravenously or intramuscularly. Each regimen must be followed by at least a trough level drawn on the third or fourth dose, 30 minutes before dosing; a peak level may be drawn 30 minutes after a 30-minute infusion.
Gentamicin is used in combination with both an agent that covers gram-positive organisms and one that covers anaerobes. It may be considered if penicillins or other less toxic drugs are contraindicated, if there are particular clinical indications for its use, or if a patient has a mixed infection caused by susceptible staphylococci and gram-negative organisms.
Clinical Context: Erythromycin is a highly bacteriostatic macrolide antibiotic isolated from a Streptomyces strain. Its spectrum is between those of penicillin and tetracyclines. The mechanism of action involves binding to the 50S ribosomal subunit and inhibiting microbial protein synthesis.
Antibiotic therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.
Dorsal view of female body louse, Pediculus humanus var corporis. This louse is a known vector responsible for transmission of epidemic typhus, trench fever, and Asiatic relapsing fever; it also causes dermatitic condition known as pediculosis. Image courtesy of Centers for Disease Control and Prevention.
Dorsal view of female body louse, Pediculus humanus var corporis. This louse is a known vector responsible for transmission of epidemic typhus, trench fever, and Asiatic relapsing fever; it also causes dermatitic condition known as pediculosis. Image courtesy of Centers for Disease Control and Prevention.
Dorsal view of female body louse, Pediculus humanus var corporis. This louse is a known vector responsible for transmission of epidemic typhus, trench fever, and Asiatic relapsing fever; it also causes dermatitic condition known as pediculosis. Image courtesy of Centers for Disease Control and Prevention.