1328 PART 5 Infectious Diseases

available; however, studies in mice suggest that ampicillin is ineffective. Drugs similar to those used against Y. enterocolitica should be

used. The best results have been obtained with a quinolone.

Some trials of treatment for reactive arthritis (with a large

proportion of cases due to Yersinia) found that 3 months of oral

ciprofloxacin therapy did not affect outcome. One trial in which

the same therapy was given specifically for Y. enterocolitica–reactive

arthritis found that, while outcome indeed was not affected, there

was a trend toward faster remission of symptoms in the treated

group. Follow-up 4–7 years after initial antibiotic treatment of

reactive arthritis (predominantly following Salmonella and Yersinia

infections) demonstrated apparent efficacy in the prevention of

chronic arthritis in HLA-B27-positive individuals. A trial showing

that azithromycin therapy did not affect outcome in reactive arthritis included cases thought to have followed yersiniosis, although no

breakdown of cases was provided.

■ PREVENTION AND CONTROL

Current control measures are similar to those used against other

enteric pathogens like Salmonella and Campylobacter, which colonize

the intestine of food animals. The focus is on safe handling and processing of food. No vaccine is effective in preventing intestinal colonization of food animals by enteropathogenic Yersinia. Consumption of

food made from raw pork (which is popular in Germany and Belgium)

should be discouraged at present because it is not possible to eliminate

contamination with the enteropathogenic Yersinia strains found worldwide in pigs. Exposure of infants to raw pig intestine during domestic

preparation of chitterlings is inadvisable. Modification of abattoir technique in Scandinavian countries from the 1990s onward included the

removal of pig intestines in a closed plastic bag; levels of carcass contamination with Y. enterocolitica were reduced, but such contamination was not eliminated. Experimental pig herds free of pathogenic Y.

enterocolitica O:3 (and also of Salmonella, Campylobacter, Toxoplasma,

and Trichinella) have been established by selective breeding in Norway

but remain rare. In the food industry, vigilance is required because of

the potential for large outbreaks if small numbers of enteropathogenic

yersiniae contaminate any ready-to-eat food whose safe preservation is

based on refrigeration before consumption.

The rare phenomenon of contamination of blood for transfusion

has proved impossible to eradicate. However, leukodepletion is now

practiced in most blood transfusion centers, primarily to prevent nonhemolytic febrile transfusion reactions and alloimmunization against

HLA antigens. This measure reduces but does not eliminate the risk of

Yersinia blood contamination.

Notification of yersiniosis is now obligatory in some countries.

■ FURTHER READING

Plague

Bertherat E: Plague around the world in 2019. Wkly Epidemiol Rec

94:289, 2019.

Campbell SB et al: Animal exposure and human plague, United States,

1970–2017. Emerg Infect Dis 25:2270, 2019.

Demeure C et al: Yersinia pestis and plague: An updated view on evolution, virulence determinants, immune subversion, vaccination and

diagnostics. Microbes Infect 21:202, 2019.

Hinnebusch BJ et al: Ecological opportunity, evolution, and the emergence of flea-borne plague. Infect Immun 84:1932, 2016.

Kool JL: Risk of person-to-person transmission of pneumonic plague.

Clin Infect Dis 40:1166, 2005.

Nelson CA et al: Antimicrobial treatment and prophylaxis of plague:

Recommendations for naturally acquired infections and bioterrorism

response. MMWR Recomm Rep 70(No. RR-3):1, 2021.

Randremanana R et al: Epidemiological characteristics of an urban

plague epidemic in Madagascar, August-November, 2017: An outbreak report. Lancet Infect Dis 19:537, 2019.

Sun W et al: Plague vaccine: Recent progress and prospects. NPJ Vaccines 4:11. 2019.

Yersiniosis

Francis MS et al: The pathogenic Yersiniae—advances in the understanding of physiology and virulence. Front Cell Infect Microbiol

9:119, 2019.

Savin C et al: Genus-wide Yersinia core-genome multilocus sequence

typing for species identification and strain characterization. Microbial Genomics 5:e000301, 2019.

Bartonella species are fastidious, facultative intracellular, slow-growing,

gram-negative bacteria that cause a broad spectrum of diseases in

humans. This genus includes >40 distinct species or subspecies, of

which at least 16 have been recognized as confirmed or potential

human pathogens; Bartonella bacilliformis, Bartonella quintana, and

Bartonella henselae are most commonly identified (Table 172-1). Most

Bartonella species have successfully adapted to survival in specific

domestic or wild mammals. Prolonged intraerythrocytic infection in

these animals creates a niche where the bacteria are protected from

both innate and adaptive immunity and which serves as a reservoir

for human infections. Bartonella characteristically evades the host

immune system by modification of its virulence factors (e.g., lipopolysaccharides or flagella) and by attenuation of the immune response. B.

bacilliformis and B. quintana, which are not zoonotic, are exceptions.

Arthropod vectors are often involved. Isolation and characterization of

Bartonella species are difficult and require special techniques. Clinical

presentation generally depends on both the infecting Bartonella species

and the immune status of the infected individual. Bartonella species are

susceptible to many antibiotics in vitro; however, clinical responses to

therapy and studies in animal models suggest that the minimal inhibitory concentrations of many antimicrobial agents correlate poorly with

the drugs’ in vivo efficacies in patients with Bartonella infections.

CAT-SCRATCH DISEASE

■ DEFINITION AND ETIOLOGY

Usually a self-limited illness, cat-scratch disease (CSD) has two general

clinical presentations. Typical CSD, the more common, is characterized

by subacute regional lymphadenopathy; atypical CSD is the collective

designation for numerous extranodal manifestations involving various

organs. B. henselae is the principal etiologic agent of CSD. Rare cases

have been associated with Afipia felis and other Bartonella species.

■ EPIDEMIOLOGY

CSD occurs worldwide, favoring warm and humid climates. In temperate climates, incidence peaks during fall and winter. Adults are affected

nearly as frequently as children. Intrafamilial clustering is rare, and

person-to-person transmission does not occur. Apparently healthy bacteremic cats constitute the major reservoir of B. henselae, and cat fleas

(Ctenocephalides felis) may be responsible for cat-to-cat transmission.

CSD usually follows contact with cats (especially kittens), but other

animals (e.g., dogs) have been implicated as possible reservoirs in rare

instances. In the United States, the estimated annual disease incidence is

~5 cases per 100,000 population. About 5% of patients are hospitalized.

■ PATHOGENESIS

Although cat fleas are likely responsible for cat-to-cat transmission, the

mode of cat-to-human transmission is undetermined. B. henselae–infected

172 Bartonella Infections,

Including Cat-Scratch

Disease

Michael Giladi, Moshe Ephros

1329CHAPTER 172 Bartonella Infections, Including Cat-Scratch Disease

cats’ saliva spreads to claws by self-licking, and B. henselae–contaminated

flea feces can be inoculated by a scratch or a bite. Infection of mucous

membranes or conjunctivae via droplets or licking may occur as well.

With lymphatic drainage to one or more regional lymph nodes in

immunocompetent hosts, a TH1 response can result in necrotizing

granulomatous lymphadenitis. Dendritic cells, along with their associated chemokines, play a role in the host inflammatory response and

granuloma formation.

■ CLINICAL MANIFESTATIONS AND PROGNOSIS

Of patients with CSD, 85–90% have typical disease. The primary lesion,

a small (0.3- to 1-cm) painless erythematous papule or pustule, develops at the inoculation site within days to 2 weeks in about one-third

to two-thirds of patients (Fig. 172-1A, B). Lymphadenopathy develops

1–3 weeks or longer after cat contact. The affected lymph node(s) are

enlarged and usually painful, sometimes have overlying erythema, and

suppurate in ~10% of cases (Fig. 172-1C, D, and E). Axillary/epitrochlear

nodes are most commonly involved, followed by head/neck nodes and

inguinal/femoral nodes. Approximately 50% of patients have fever,

malaise, and anorexia. A smaller proportion experience weight loss and

night sweats mimicking the presentation of lymphoma. Fever is usually

low-grade but infrequently rises to ≥39°C. Resolution is slow, requiring weeks (for fever, pain, and accompanying signs and symptoms) to

months (for node shrinkage).

Atypical CSD occurs in 10–15% of patients in the absence or presence

of lymphadenopathy. Atypical disease includes Parinaud’s oculoglandular syndrome (granulomatous conjunctivitis with ipsilateral preauricular

lymphadenitis; Fig. 172-1E), hepatosplenic disease, neuroretinitis (often

presenting as unilateral deterioration of vision; Fig. 172-1F) and other

ophthalmologic manifestations, neurologic manifestations (encephalitis, seizures, myelitis, cerebellitis, facial and other cranial or peripheral

palsies), fever of unknown origin, pneumonitis, debilitating myalgia,

arthritis or arthralgia (affecting mostly women >20 years old), osteomyelitis (including multifocal disease), tendinitis, and dermatologic manifestations (including erythema nodosum [see Fig. A1-39], sometimes

TABLE 172-1 Bartonella Species Known or Suspected to Be Human Pathogens

BARTONELLA SPECIESa DISEASE(S)b RESERVOIR HOST(S)c ARTHROPOD VECTOR

B. henselae Cat-scratch disease, bacillary

angiomatosis, bacillary peliosis,

bacteremia, endocarditis

Cats, other felines Cat fleas (Ctenocephalides felis):

associated with cat-to-cat, but not with

cat-to-human, transmission

B. quintana Trench fever, chronic bacteremia,

bacillary angiomatosis, endocarditis

Humans Human body lice (Pediculus humanus

corporis)

B. bacilliformis Carrión’s disease Humans Sandflies (Lutzomyia verrucarum)

B. elizabethae Endocarditis Rats, dogs Unknown

B. grahamiid Lymphadenopathy Mice, voles Fleas

B. vinsonii subsp. arupensis Endocarditis, febrile illness Mice, dogs Ticks

B. vinsonii subsp. berkhoffii Endocarditis Domestic dogs, coyotes, gray foxes Ticks

B. washoensis Endocarditis, myocarditis, meningitis Squirrels, possibly other rodents Fleas

B. alsatica Endocarditis, lymphadenitis, vascular

graft infection

Rabbits Fleas

B. koehlerae Endocarditis Cats Unknown

B. clarridgeiae Possibly cat-scratch disease Cats Unknown

B. rochalimae Bacteremia, fever, splenomegaly Unknown Possibly fleas

B. tamiae Bacteremia, fever, myalgia, rash Unknown Unknown

B. melophagi Various clinical manifestations Sheep Sheep keds

B. ancashensis Verruga peruana Unknown Unknown

Candidatus B. mayotimonensise Endocarditis Bats Unknown

a

Many other Bartonella species exist but are not recognized as human pathogens. b

Animal-associated Bartonella species (B. henselae, B. doshiae, B. schoenbuchensis,

and B. tribocorum) were isolated from blood of patients who reported tick bites and chronic symptoms such as fatigue and myalgia. DNA of B. henselae, B. vinsonii subsp.

berkhoffii, B. koehlerae, or B. melophagi or co-infection with more than one Bartonella species was detected by polymerase chain reaction in blood samples from patients

with extensive arthropod and animal exposure who presented with chronic neurologic or neurocognitive syndromes. The causal relationship between bacteremia with

these pathogens, tick bites, and clinical manifestations needs to be established. c

Animals are implicated when existing evidence supports their infection with Bartonella

species. Data supporting animal-to-human transmission may be lacking. d

Retinitis may also be associated with B. grahamii. e

Candidatus is a taxonomic status for bacteria

that cannot be described in sufficient detail to warrant establishment of a novel taxon or cannot be cultured or propagated in culture media. The phylogenetic relatedness

of these bacteria has been determined by gene amplification and sequence analysis.

accompanying arthropathy). CSD-associated fever of unknown origin

is a unique syndrome that may be severe and debilitating, often mimics

malignancy, and may present with multiorgan involvement, including

hepatosplenic space-occupying lesions, abdominal/mediastinal lymphadenopathy, ocular disease, and multifocal osteomyelitis. Fever may be

continuous or relapsing. Other manifestations and syndromes (pleural

effusion, idiopathic thrombocytopenic purpura, Henoch-Schönlein

purpura, erythema multiforme [see Fig. A1-24], glomerulonephritis,

myocarditis) have also been associated with CSD. In elderly patients

(>60 years old), lymphadenopathy is more often absent but encephalitis and fever of unknown origin are more common than in younger

patients. In immunocompetent individuals, CSD—whether typical or

atypical—usually resolves without treatment and without sequelae,

although some of the ophthalmologic manifestations may occasionally

result in moderate to severe vision loss. Lifelong immunity is the rule.

■ DIAGNOSIS

Routine laboratory tests usually yield normal or nonspecific results.

Histopathology initially shows lymphoid hyperplasia and later demonstrates stellate granulomata with necrosis, coalescing microabscesses,

and occasional multinucleated giant cells—findings that, although

nonspecific, may narrow the differential diagnosis. Serologic testing

(immunofluorescence or enzyme immunoassay) is the most commonly used laboratory diagnostic approach, with variable sensitivity

and specificity. CSD serodiagnosis is often based on the presence of

IgG alone (i.e., in the absence of IgM), and seroconversion may take a

few weeks; these two factors may pose difficulties in the interpretation

of serologic results. Other tests are of low sensitivity (culture, WarthinStarry silver staining), of low specificity (cytology, histopathology), or

of limited availability in routine diagnostic laboratories (polymerase

chain reaction [PCR], immunohistochemistry). PCR of pus aspirated

from lymph nodes or the primary inoculation lesion is highly sensitive

and specific and is particularly useful for definitive and rapid diagnosis

in seronegative patients. PCR of a lymph node biopsy specimen may be

less sensitive, perhaps because of sampling error.

1330 PART 5 Infectious Diseases

FIGURE 172-1 Manifestations of cat-scratch disease. A. Primary inoculation

lesion. Axillary and epitrochlear lymphadenitis appeared 2 weeks later. B. Primary

inoculation lesion. Submental lymphadenitis appeared 10 days later. C. Axillary

lymphadenopathy of 2 weeks’ duration. The overlying skin appears normal. D.

Cervical lymphadenopathy of 6 weeks’ duration. The overlying skin is red. Thick,

odorless pus (12 mL) was aspirated. E. Preauricular lymphadenopathy. F. Left-eye

neuroretinitis. Note papilledema and stellate macular exudates (“macular star”).

A

B

C

D

E

F

1331CHAPTER 172 Bartonella Infections, Including Cat-Scratch Disease

APPROACH TO THE PATIENT

Cat-Scratch Disease

A history of cat contact, a primary inoculation lesion, and regional

lymphadenopathy—especially axillary/epitrochlear lymphadenopathy—are highly suggestive of CSD. A characteristic clinical course and

corroborative laboratory tests make the diagnosis very likely. Conversely,

when acute- and convalescent-phase sera are negative (as is the case in

10–20% of CSD patients), when spontaneous regression of lymph node

size does not occur, and particularly when constitutional symptoms

persist, malignancy must be ruled out. Pyogenic lymphadenitis, mycobacterial infection, brucellosis, syphilis, tularemia, plague, toxoplasmosis, sporotrichosis, and histoplasmosis should also be considered. In

clinically suspected CSD in a seronegative individual, fine-needle aspiration may be adequate and PCR can confirm the diagnosis. When data

are less supportive of CSD, lymph node biopsy rather than fine-needle

aspiration is preferred. In seronegative CSD patients with lymphadenopathy and severe complications (e.g., encephalitis or neuroretinitis),

early biopsy is important to establish a specific diagnosis.

TREATMENT

Cat-Scratch Disease

(Table 172-2) Treatment regimens are based on only minimal data.

Suppurative nodes should be drained by large-bore needle aspiration and not by incision and drainage to avoid chronic draining

tracts. Systemic antibiotics are recommended in immunocompromised patients.

■ PREVENTION

Avoiding cats (especially kittens) and instituting flea control are

options for immunocompromised patients and for patients with valvular heart disease.

TRENCH FEVER AND CHRONIC

BACTEREMIA

■ DEFINITION AND ETIOLOGY

Trench fever, also known as 5-day fever or quintan fever, is a febrile illness caused by B. quintana. It was first described as an epidemic in the

trenches of World War I; however, recent paleomicrobiological studies

have provided evidence that B. quintana has been associated with

human infection for 4000 years. This infection recently reemerged as

chronic bacteremia seen most often in homeless people, also referred

to as urban or contemporary trench fever.

■ EPIDEMIOLOGY

In addition to epidemics during World Wars I and II, sporadic outbreaks of trench fever have been reported in many regions of the world.

The human body louse has been identified as the vector and humans

as the only known reservoir. After a hiatus of several decades during

which trench fever was almost forgotten, small clusters of cases of B.

quintana chronic bacteremia were reported sporadically, primarily

from the United States and France, in HIV-uninfected homeless people. Alcoholism and louse infestation were identified as risk factors.

■ CLINICAL MANIFESTATIONS

The typical incubation period is 15–25 days (range, 3–38 days). “Classical” trench fever, as described in 1919, ranges from a mild febrile illness

to a recurrent or protracted and debilitating disease. Fever is often periodic, lasting 4–5 days with 5-day (range, 3- to 8-day) intervals between

episodes. Other symptoms and signs include headache, back and limb

pain, profuse sweating, shivering, myalgia, arthralgia, splenomegaly, a

maculopapular rash in occasional cases, and nuchal rigidity in some

cases. Untreated, the disease usually lasts 4–6 weeks. Death is rare. The

clinical spectrum of B. quintana bacteremia in homeless people ranges

from asymptomatic infection to a febrile illness with headache, severe

leg pain, and thrombocytopenia. Endocarditis sometimes develops.

TABLE 172-2 Antimicrobial Therapy for Disease Caused by Bartonella

Species in Adults

DISEASE ANTIMICROBIAL THERAPY

Typical cat-scratch

disease

Not routinely indicated; for patients with extensive

lymphadenopathy, consider azithromycin (500 mg PO on

day 1, then 250 mg PO once a day for 4 days)

Cat-scratch disease

neuroretinitis

Value of systemic antibiotics is controversial, particularly

when visual acuity is not significantly compromised. For

more severe cases, doxycycline (100 mg PO bid) plus

rifampin (300 mg PO bid) for 4–6 weeks is given. Consider

adding systemic glucocorticoids.

Other atypical catscratch disease

manifestationsa

As per neuroretinitis. Treatment duration should be

individualized.

Trench fever or

chronic bacteremia

with B. quintana

Gentamicin (3 mg/kg IV once a day for 14 days) plus

doxycycline (200 mg PO once a day or 100 mg PO bid for

6 weeks)

Suspected Bartonella

endocarditis

Gentamicinb

 (1 mg/kg IV q8h for ≥14 days) plus

doxycycline (100 mg PO/IV bid for 6 weeksc

) plus

ceftriaxone (2 g IV once a day for 6 weeks)

Confirmed Bartonella

endocarditis

As for suspected Bartonella endocarditis minus

ceftriaxone

Bacillary

angiomatosis

Erythromycind

 (500 mg PO qid for 3 months)

or

Doxycycline (100 mg PO bid for 3 months)

Bacillary peliosis Erythromycind

 (500 mg PO qid for 4 months)

or

Doxycycline (100 mg PO bid for 4 months)

Carrión’s disease

Oroya fever Chloramphenicol (500 mg PO/IV qid for 14 days) plus

another antibiotic (β-lactam preferred)

or

Ciprofloxacin (500 mg PO bid for 10 days) +/– ceftriaxone

(1–2 g IV once a day for 10 days)

Verruga peruana Azithromycin (500 mg PO once a day for 7 days)

or

Ciprofloxacin (500 mg PO bid for 7–10 days)

or

Rifampin (10 mg/kg PO once a day, to a maximum of

600 mg, for 14 days)

or

Streptomycin (15–20 mg/kg IM once a day for 10 days)

a

Data on treatment efficacy for encephalitis and hepatosplenic cat-scratch

disease are lacking. Therapy similar to that given for neuroretinitis is reasonable.

b

Some experts recommend gentamicin at 3 mg/kg IV once a day. If gentamicin

is contraindicated, rifampin (300 mg PO bid) can be added to doxycycline for

documented Bartonella endocarditis. c

Some experts recommend extending oral

doxycycline therapy for 3–6 months. d

Other macrolides are probably effective and

may be substituted for erythromycin or doxycycline.

Source: Recommendations are modified from JM Rolain et al: Antimicrob Agents

Chemother 48:1921, 2004.

■ DIAGNOSIS

Definitive diagnosis requires isolation of B. quintana by blood culture.

Some patients have positive blood cultures for several weeks. Patients

with acute trench fever typically develop significant titers of antibody

to Bartonella, whereas those with chronic B. quintana bacteremia may

be seronegative. Patients with high titers of IgG antibodies should be

evaluated for endocarditis. In epidemics, trench fever should be differentiated from epidemic louse-borne typhus and relapsing fever, which

occur under similar conditions and share many features.

TREATMENT

B. quintana Bacteremia

(Table 172-2) In a small, randomized, placebo-controlled trial

involving homeless people with B. quintana bacteremia, therapy

with gentamicin and doxycycline was superior to administration

1332 PART 5 Infectious Diseases

of placebo in eradicating bacteremia. Treatment of bacteremia is

important, even in clinically mild cases, to prevent endocarditis.

Optimal therapy for trench fever without documented bacteremia

is uncertain.

BARTONELLA ENDOCARDITIS

■ DEFINITION AND ETIOLOGY

Coxiella burnetii (Chap. 187) and Bartonella species are the most

common pathogens in culture-negative endocarditis (Chap. 128). In

France, for example, Bartonella species were identified as the etiologic

agents in 28% of 348 cases of culture-negative endocarditis. Prevalence,

however, varies by geographic location and epidemiologic setting. In

addition to B. quintana and B. henselae (the most common Bartonella

species implicated in endocarditis, the former more commonly than

the latter), other Bartonella species have reportedly caused rare cases

(Table 172-1).

■ EPIDEMIOLOGY

Bartonella endocarditis has been reported worldwide. Most patients

are adults; more are male than female. Risk factors associated with

B. quintana endocarditis include homelessness, alcoholism, and body

louse infestation; however, individuals with no risk factors have had

Bartonella endocarditis diagnosed as well. B. henselae endocarditis is

associated with exposure to cats. Most cases involve native rather than

prosthetic valves; the aortic valve accounts for ~60% of cases. Patients

with B. henselae endocarditis usually have preexisting valvulopathy,

whereas B. quintana often infects normal valves.

■ CLINICAL MANIFESTATIONS

Clinical manifestations are usually characteristic of subacute endocarditis of any etiology. However, a substantial number of patients have a

prolonged, minimally febrile or even afebrile indolent illness, with mild

nonspecific symptoms lasting weeks or months before the diagnosis

is made. Initial echocardiography may not show vegetations. Acute,

aggressive disease is rare.

■ DIAGNOSIS

Blood cultures, even with use of special techniques (lysis centrifugation

or EDTA-containing tubes), are positive in only ~25% of cases—mostly

those caused by B. quintana and only rarely those caused by B. henselae.

Prolonged incubation of cultures (up to 6 weeks) is required. Serologic

tests—either immunofluorescence or enzyme immunoassay—usually

demonstrate high-titer (≥1:800) IgG antibodies to Bartonella. Because

of cross-antigenicity, routine serology does not distinguish between B.

quintana and B. henselae and may also be low-titer cross-reactive with

other pathogens, such as C. burnetii and Chlamydia species. Identification of Bartonella to the species level is usually accomplished by application of PCR and DNA sequencing methods to valve tissue.

TREATMENT

Bartonella Endocarditis

(Table 172-2) For patients with culture-negative endocarditis suspected to be due to Bartonella species, empirical treatment consists

of gentamicin, doxycycline, and ceftriaxone; the major role of ceftriaxone in this regimen is to adequately treat other potential causes

of culture-negative endocarditis, including members of the HACEK

group (Chap. 158). Once a diagnosis of Bartonella endocarditis has

been established, ceftriaxone is discontinued. Aminoglycosides, the

only antibiotics known to be bactericidal against Bartonella, should

be included in the regimen for ≥2 weeks. Indications for valvular

surgery are the same as in subacute endocarditis due to other pathogens; however, the proportion of patients who undergo surgery

(~60%) is high, probably as a consequence of delayed diagnosis.

BACILLARY ANGIOMATOSIS AND PELIOSIS

■ DEFINITION AND ETIOLOGY

Bacillary angiomatosis (sometimes called bacillary epithelioid angiomatosis or epithelioid angiomatosis) is a disease of severely immunocompromised patients, is caused by B. henselae or B. quintana, and

is characterized by neovascular proliferative lesions involving various

organs. Both species cause cutaneous lesions; hepatosplenic lesions

are caused only by B. henselae, whereas subcutaneous and lytic bone

lesions are more frequently associated with B. quintana. Bacillary

peliosis is a closely related angioproliferative disorder caused by B.

henselae and involving primarily the liver (peliosis hepatis) but also the

spleen and lymph nodes. Bacillary peliosis is characterized by bloodfilled cystic structures whose size ranges from microscopic to several

millimeters.

■ EPIDEMIOLOGY

Bacillary angiomatosis and bacillary peliosis occur primarily in

HIV-infected persons (Chap. 202) with CD4+ T-cell counts of <100/μL

but also affect other immunosuppressed patients and, in rare instances,

immunocompetent patients. The incidence has decreased since the

introduction of effective antiretroviral therapy and the routine use of

rifabutin and macrolides to prevent Mycobacterium avium complex

infection in AIDS patients. Contact with cats or cat fleas increases the

risk of B. henselae infection. Risk factors for B. quintana infection are

low income, homelessness, and body louse infestation.

■ CLINICAL MANIFESTATIONS

Bacillary angiomatosis presents most commonly as one or more

cutaneous lesions that are not painful and may be tan, red, or purple

in color. Subcutaneous, often tender nodules, superficial ulcerated

plaques (Fig. 172-2), and verrucous growths are also seen. Nodular

forms resemble those seen in fungal or mycobacterial infections.

Painful osseous lesions, most often involving long bones, may underlie

cutaneous lesions and occasionally develop in their absence. Other

organs are rarely involved. Patients usually have constitutional symptoms, including fever, chills, malaise, headache, anorexia, weight loss,

and night sweats. In patients with advanced immunodeficiency, B.

henselae and B. quintana are important causes of fever of unknown origin. In osseous disease, lytic lesions are generally seen on radiography,

and technetium scan shows focal uptake. The differential diagnosis of

cutaneous bacillary angiomatosis includes Kaposi’s sarcoma, pyogenic

granuloma, subcutaneous tumors, and verruga peruana. In bacillary

peliosis, hypodense hepatic areas are usually evident on imaging.

■ PATHOLOGY

Bacillary angiomatosis consists of lobular proliferations of small blood

vessels lined by enlarged endothelial cells interspersed with mixed

infiltrates of neutrophils and lymphocytes, with predominance of the

former. Histologic examination of organs with bacillary peliosis reveals

small blood-filled cystic lesions partially lined by endothelial cells that

can be several millimeters in size. Peliotic lesions are surrounded by

fibromyxoid stroma containing inflammatory cells, dilated capillaries,

and clumps of granular material. Warthin-Starry silver staining of

bacillary angiomatosis and peliosis lesions reveals clusters of bacilli.

Cultures are usually negative.

■ DIAGNOSIS

Bacillary angiomatosis and bacillary peliosis are diagnosed by histologic examination. Blood cultures may be positive.

TREATMENT

Bacillary Angiomatosis and Peliosis

(Table 172-2) Prolonged therapy with a macrolide or doxycycline

is recommended for both bacillary angiomatosis and bacillary

peliosis.

1333CHAPTER 172 Bartonella Infections, Including Cat-Scratch Disease

■ PREVENTION

Reasonable strategies for HIV-infected persons consist of control of

cat-flea infestation and avoidance of cat scratches (for prevention of B.

henselae) and avoidance and treatment of body louse infestation (for

prevention of B. quintana). Primary prophylaxis is not recommended,

but suppressive therapy with a macrolide or doxycycline is indicated in

HIV-infected patients with bacillary angiomatosis or bacillary peliosis

until CD4+ T-cell counts are >200/μL. Relapse may necessitate lifelong

suppressive therapy in individual cases.

CARRIÓN’S DISEASE (OROYA FEVER AND

VERRUGA PERUANA)

■ DEFINITION AND ETIOLOGY

Carrión’s disease is a biphasic disease caused by B. bacilliformis. Oroya

fever is the initial, bacteremic, systemic form, and verruga peruana is

its late-onset, eruptive manifestation.

■ EPIDEMIOLOGY AND PREVENTION

Infection is endemic to the geographically restricted Andes valleys of

Peru, Ecuador, and Colombia (~500–3200 m above sea level). Sporadic

epidemics occur. The disease is transmitted by the phlebotomine

sandfly Lutzomyia verrucarum. Maternal-fetal transmission as well as

transmission by blood transfusion have been reported. Humans are

the only known reservoir of B. bacilliformis. Sandfly control measures

(e.g., insecticides) and personal protection measures (e.g., repellents,

screening, bed nets) may decrease the risk of infection.

■ PATHOGENESIS

After inoculation by the sandfly, bacteria invade the blood vessel

endothelium and proliferate; the reticuloendothelial system and various organs may also be involved. Upon reentry into blood vessels,

B. bacilliformis invades, replicates, and ultimately destroys erythrocytes, with consequent massive hemolysis and sudden, severe anemia.

Microvascular thrombosis results in end-organ ischemia. Survivors

sometimes develop cutaneous hemangiomatous lesions characterized

by various inflammatory cells, endothelial proliferation, and the presence of B. bacilliformis (verruga peruana).

■ CLINICAL MANIFESTATIONS

The incubation period is 3 weeks (range, 2–14 weeks). Oroya fever may

present as a nonspecific bacteremic febrile illness without anemia or as

an acute, severe hemolytic anemia with hepatomegaly and jaundice of

rapid onset leading to vascular collapse and clouded sensorium. Myalgia, arthralgia, lymphadenopathy, and abdominal pain may develop.

Temperature is elevated but not extremely so; high fever may suggest

intercurrent infection. Subclinical asymptomatic infection also occurs.

In verruga peruana, red, hemangioma-like, cutaneous vascular lesions

of various sizes appear either weeks to months after systemic illness or

with no previous suggestive history. These lesions persist for months

up to 1 year. Mucosal and internal lesions may also develop.

■ DIAGNOSIS AND APPROACH TO THE PATIENT

Systemic illness (with or without anemia) or the development of cutaneous lesions in a person who has been to an endemic area raises the

possibility of B. bacilliformis infection. Severe anemia with exuberant

reticulocytosis—and sometimes thrombocytopenia—can occur. In systemic illness, Giemsa-stained blood films may show typical intraerythrocytic bacilli. Blood and bone marrow cultures may be positive, but

growth is slow (1−6 weeks) and requires lower incubation temperature.

Serologic assays may be helpful. Diagnosis of verruga peruana is largely

clinical, although biopsy may be required to confirm the diagnosis.

Several PCR assays have been described; however, their role in diagnosis remains to be clinically validated. Differential diagnosis includes

coendemic systemic febrile illnesses (e.g., typhoid fever, malaria,

brucellosis) and diseases producing cutaneous vascular lesions (e.g.,

hemangiomata, bacillary angiomatosis, Kaposi’s sarcoma).

FIGURE 172-2 Lesions of cutaneous bacillary angiomatosis (BA) in three severely immunocompromised AIDS patients. Left panel shows a 1.5-cm ulcerated, bleeding BA

lesion with an erythematous base; middle panel shows numerous small, 2-mm, scattered angiomatous BA lesions; right panel shows a 2.0-cm friable BA lesion on the thigh.

(Photos courtesy of Timothy Berger, MD; Jordan Tappero, MD, MPH; and Jane Koehler, MA, MD.)

1334 PART 5 Infectious Diseases

Donovanosis is a chronic, progressive bacterial infection that usually

involves the genital region. The condition is generally regarded as a

sexually transmitted infection of low infectivity. This infection has

been known by many other names, the most common being granuloma

inguinale.

■ ETIOLOGY

The causative organism has been reclassified as Klebsiella granulomatis

comb nov on the basis of phylogenetic analysis, although there is ongoing debate about this decision. Some authorities consider the original

nomenclature (Calymmatobacterium granulomatis) to be more appropriate in light of analysis of 16S rRNA gene sequences.

Donovanosis was first described in Calcutta in 1882, and the causative organism was recognized by Charles Donovan in Madras in 1905.

He identified the characteristic Donovan bodies, measuring 1.5 ×

0.7 μm, in macrophages and the stratum malpighii. The organism

was not reproducibly cultured until the mid-1990s, when its isolation

in peripheral-blood monocytes and human epithelial cell lines was

reported.

173 Donovanosis

Nigel O’Farrell

FIGURE 173-1 Ulcerogranulomatous penile lesion of donovanosis, with some

hypertrophic features.

TREATMENT

Carrión’s Disease

(Table 172-2) Antibiotic therapy for systemic B. bacilliformis infection usually results in rapid defervescence. Additional antibiotic

treatment of intercurrent infection (particularly salmonellosis) is

often required. Blood transfusion may be necessary. Treatment

of verruga peruana usually is not always required. Patients with

numerous lesions, especially lesions that have been present for only

a short period, may respond well to antibiotic therapy.

■ COMPLICATIONS AND PROGNOSIS

Mortality rates associated with Oroya fever have been reported to be as

high as 40% without treatment but are considerably lower (~10%) with

treatment. Complications such as bacterial superinfection and neurologic and cardiac manifestations occur frequently. Generalized massive

edema (anasarca) and petechiae are associated with poor outcome.

Permanent immunity usually develops.

■ FURTHER READING

Deng H et al: Molecular mechanisms of Bartonella and mammalian

erythrocyte interactions: A review. Front Cell Infect Microbiol 8:431,

2018.

Fournier PE et al: Epidemiologic and clinical characteristics of Bartonella quintana and Bartonella henselae endocarditis: A study of 48

patients. Medicine (Baltimore) 80:245, 2001.

Gomes C, Ruiz J: Carrion’s disease: The sound of silence. Clin Microbiol Rev 31:e56, 2018.

Koehler JE et al: Molecular epidemiology of Bartonella infections in

patients with bacillary angiomatosis-peliosis. N Engl J Med 337:1876,

1997.

Landes M et al: Cat scratch disease presenting as fever of unknown

origin is a unique clinical syndrome. Clin Infect Dis 71:2818, 2020.

Rolain JM et al: Recommendations for treatment of human infections

caused by Bartonella species. Antimicrob Agents Chemother 48:1921,

2004.

Rose SR, Koehler JE: Bartonella including cat scratch disease, in

Principles and Practice of Infectious Diseases, 9th ed, GL Mandell et al

(eds). Philadelphia, Elsevier, Inc. 2020, pp 2824-2843.

■ EPIDEMIOLOGY

Donovanosis has an unusual geographic distribution that has included

Papua New Guinea, parts of southern Africa, India, the Caribbean,

French Guyana, Brazil, and Aboriginal communities in Australia. In

Australia, donovanosis has been almost entirely eliminated through

a sustained program backed by strong political commitment and

resources at the primary health care level. In South Africa, donovanosis is also very close to elimination. Although few cases are now

reported in the United States, donovanosis was once prevalent in this

country, with 5000–10,000 cases recorded in 1947. The largest epidemic recorded was in Dutch South Guinea, where 10,000 cases were

identified in a population of 15,000 (the Marind-anim) between 1922

and 1952.

Donovanosis is associated with poor hygiene and is more common

in lower socioeconomic groups than in those who are better off and in

men than in women. Infection in sexual partners of index cases occurs

to a limited extent. Donovanosis is a risk factor for HIV infection

(Chap. 202).

Globally, the incidence of donovanosis has decreased significantly in

recent times. This decline probably reflects a greater focus on effective

management of genital ulcers because of their role in facilitating HIV

transmission.

■ CLINICAL FEATURES

A lesion starts as a papule or subcutaneous nodule that later ulcerates

after trauma. The incubation period is uncertain, but experimental

infections in humans indicate a duration of ~50 days. Four types of

lesions have been described: (1) the classic ulcerogranulomatous lesion

(Fig. 173-1), a beefy red ulcer that bleeds readily when touched; (2)

a hypertrophic or verrucous ulcer with a raised irregular edge; (3) a

necrotic, offensive-smelling ulcer causing tissue destruction; and (4) a

sclerotic or cicatricial lesion with fibrous and scar tissue.

The genitals are affected in 90% of patients and the inguinal region

in 10%. The most common sites of infection are the prepuce, coronal

sulcus, frenum, and glans in men and the labia minora and fourchette

in women. Cervical lesions may mimic cervical carcinoma. In men,

lesions are associated with lack of circumcision. Lymphadenitis is

uncommon. Extragenital lesions occur in 6% of cases and may involve

the lip, gums, cheek, palate, pharynx, larynx, and chest. Hematogenous

spread with involvement of liver and bone has been reported. During

pregnancy, lesions tend to develop more quickly and respond more

slowly to treatment. Polyarthritis and osteomyelitis are rare complications. In newborn infants, donovanosis may present with ear infection.

Cases in children have been attributed to sitting on the laps of infected

adults. As the incidence of donovanosis has decreased, the number of

unusual case reports has appeared to be increasing.

Complications include neoplastic changes, pseudoelephantiasis, and

stenosis of the urethra, vagina, or anus.