Bartonella, Legionella, Mycoplasma, and Ureaplasma

Epidemiology and risk factors

Bartonella species are fastidious, slow-growing, gram-negative bacilli. There are 45 different species that can cause disease in zoonotic hosts, with Bartonella henselae and Bartonella quintana causing most Bartonella -related disease in human hosts in the United States. B. henselae has been reported to cause infection in pediatric and adult heart, liver, and renal transplant recipients and in adult lung transplant recipients. There have been rare reports of B. quintana causing disease in adult solid organ transplant (SOT) recipients. Both species have been reported to cause infection in pediatric patients undergoing chemotherapy for hematologic malignancies.

Cat-scratch disease (CSD), a syndrome of regional lymphadenopathy or granulomatous disease in the liver and spleen, is the most widely recognized illness attributed to B. henselae . The highest incidence of CSD in the United States is reported in people who live in the Southeast and among children 5 to 9 years of age. Granulomatous disease/CSD is the most common presentation of B. henselae in SOT recipients and is found in 19 of 32 (59%) reported cases. B henselae infection disproportionately affects children. Moulin and colleagues reported that 25% of the cases of Bartonella infection in transplant recipients occurred in children younger than 18 years, despite pediatric patients representing only 3% to 4% of the overall transplant population.

Bacillary angiomatosis (BA) and bacillary peliosis (BP) are vasoproliferative manifestations of both B. henselae and B. quintana in immunocompromised hosts. They are most commonly described in adults with very low CD4 ⁺ lymphocyte counts caused by human immunodeficiency virus (HIV). Cases have been described in pediatric and adult SOT recipients and those with hematologic malignancies. All patients reported with BA associated with cancer have had full resolution of their disease with treatment. Interestingly, in SOT recipients, BA tends to develop on average 1.9 years after transplantation, whereas granulomatous disease/CSD develops 5.2 years after transplantation. The reason for this is unknown but may be explained by greater immunosuppression close to the time of transplant, predisposing patients to vasoproliferative manifestations.

B. henselae causes bacteremia in cats, its natural reservoir. The seroprevalence of B. henselae is 13% to 90% in domestic and stray cats in the United States. Other animals, including dogs, can become infected and have been associated with human disease. Kittens and stray or sheltered cats are more likely to have bacteremia, which can last for weeks to months. Despite this, cats are usually asymptomatic. Transmission between cats occurs through the cat flea, whereas transmission to humans occurs through the lick, bite, or scratch of a bacteremic cat; the claws of the cat are thought to be contaminated by the feces of Bartonella -infected fleas. The incubation period from scratch to the appearance of a cutaneous lesion is 7 to 12 days. Lymphadenopathy usually occurs 5 to 50 days, with a median of 12 days, after the scratch.

There have been no cases of person-to-person B. henselae transmission. One case of possible donor-derived transmission has been reported in an asymptomatic liver transplant recipient with granulomatous hepatic lesions appearing 2 months after transplant. Subsequent 16S PCR of DNA from the lesion was positive for B. henselae . This patient had no reported contact with cats, raising the possibility of donor-derived infection.

B. quintana is closely related to B. henselae and is more commonly associated with louse-borne trench fever. Risk factors for infection with B. quintana include homelessness, chronic alcoholism, and body lice.

Clinical manifestations

In general, Bartonella -mediated disease in transplant recipients can be divided into two distinct groups: cat-scratch disease (typical and disseminated) and BA and BP.

Cat-scratch disease commonly occurs in immunocompetent children as a self-limited febrile illness characterized by a cutaneous papule at the site of a cat scratch and accompanied by regional lymphadenopathy. Cases of this “typical” regional presentation of CSD have also been reported in pediatric SOT recipients. ^, Lymph nodes are generally tender and can have central necrosis and suppuration. Nodes may regress spontaneously within 2 to 4 months in immunocompetent hosts, but usually respond promptly to antimicrobial therapy in SOT patients. Systemic symptoms are mild in immunocompetent hosts, whereas transplant recipients can present with fever, fatigue, myalgias, joint pain, and night sweats. Importantly, although fever is the most common symptom present in any manifestation of Bartonella disease in SOT recipients, the absence of fever does not rule out this infection. At least two cases of B. henselae infection without fever have been reported in children, ^, with another two cases reported in adults, one of whom died from infective endocarditis.

Lymphadenopathy can also be accompanied by hepatosplenic lesions, concerning for disseminated disease in SOT recipients. Children often present with prolonged fever, abdominal pain, joint pain, headache, weight loss, and chills. Immunocompromised patients may have splenic or hepatic enlargement or both, and abdominal imaging usually identifies hypodense lesions in either or both organs. Transaminase levels often remain normal. In almost all cases, cat, kitten, or flea exposure is given in the history. Recurrence has been reported, with one case of recurrent cat-scratch lymphadenitis described in a pediatric kidney transplant recipient. More unusual manifestations of CSD in immunocompetent hosts include endocarditis, osteomyelitis, encephalopathy, retinitis, optic neuritis, and Parinaud oculoglandular syndrome. A case of posterior uveitis and one case of pulmonary nodules caused by B. henselae have been described in pediatric kidney transplant recipients. Acute rejection of the renal allograft has been reported in conjunction with Bartonella infection in two children. Reports in adult renal transplant recipients have described a patient with sternal abscess and one with septic shock, encephalopathy and seizures, and bacteremia has been described in a hematopoietic stem cell transplant (HSCT) recipient.

BA and BP vasculoproliferative cutaneous or subcutaneous lesions are due to either B. henselae or B. quintana . Lesions of BA are most commonly seen on the skin but may involve subdermal structures, bones, and mucous membranes of the mouth, conjunctivae, and the gastrointestinal tract. BP lesions may appear as hemorrhagic parenchymous and cystic lesions usually seen in the liver or spleen. B. henselae is almost exclusively associated with lesions in the lymph nodes and the liver, whereas bone lesions are more associated with B. quintana . Children may be systemically asymptomatic, or more commonly, present similarly to those with CSD with systemic symptoms of fever, abdominal pain, anorexia, myalgias, nausea, vomiting, weight loss, night sweats, and weakness. Liver and spleen lesions, lymphadenopathy, and hepatomegaly have also been reported. ^, Vasculoproliferative cutaneous lesions can be papular, nodular, or vascular; are usually red or violaceous in color; and may be hemorrhagic, ulcerating, or have a collarette of scale. They can be solitary or multiple and may grossly resemble Kaposi sarcoma. Recurrence of BA is seen in HIV-positive patients and has been described in a pediatric renal transplant recipient despite prolonged therapy for the first episode. ^,

Providers should also have a low index of suspicion for secondary hemophagocytic lymphohistiocytosis in transplant recipients with Bartonella infection, as it has been described in both children and adults. ^, Pancytopenias, elevated transaminase levels, low fibrinogen level, and a very elevated ferritin level should prompt the clinician to consider this diagnosis. Treatment of the underlying cause is prudent, but patients may also require corticosteroid therapy. Consultation with a hematologist may be warranted.

Disease prophylaxis/prevention

Because cats and kittens carry B. henselae and because cat fleas play a major role in cat-to-cat transmission, it is prudent to discuss pet ownership with transplant recipients and their families. They should be educated about obtaining and caring for pets, particularly cats and kittens. All pets should be seen regularly by a veterinarian and before introduction of the pet into the home. Flea control is essential. New pets should not be introduced during times of heightened immunosuppression (immediate posttransplant period or during treatment for rejection). Immunocompromised hosts should avoid all contact with cats younger than 1 year, stray cats, cats with fleas, or cats that bite or scratch. Although declawing of cats is not routinely recommended, patients should not engage in behavior that would cause a scratch or bite. If a scratch or bite should occur, it should be cleaned immediately and thoroughly. Testing cats for Bartonella infection is not recommended because cats can be transiently bacteremic. Good hand hygiene is always encouraged, especially after petting or caring for cats or kittens.

Diagnosis

The differential diagnosis of cat scratch disease includes other causes of lymphadenopathy and systemic symptoms in transplant recipients: cytomegalovirus, Epstein-Barr virus, and posttransplant lymphoproliferative disease, lymphoma, fungal or mycobacterial infections, and pyogenic abscesses. BA may mimic Kaposi sarcoma, pyogenic granuloma, or angiosarcoma. Bartonella infection should be considered in any transplant recipient with cat or cat flea exposure who presents with unexplained fever, culture-negative endocarditis, granulomatous or necrotic regional or disseminated lymphadenopathy, BA or BP, new hepatomegaly, new splenomegaly, or hepatosplenic lesions.

Confirmatory diagnosis can be challenging in immunosuppressed patients. The indirect immunofluorescent antibody assay for detection of serum antibodies to antigens of Bartonella species is available at many commercial laboratories and through the Centers for Disease Control and Prevention. Immunoglobulin (Ig) M production is brief and may easily be missed. Immunofluorescent antibody IgG titer greater than 1:256 is consistent with acute infection, although lower titers (>1:64) have been used for diagnosis. Documentation of a fourfold increase in IgG titers can also be suggestive of recent infection. In one review of the literature, of 23 SOT patients with Bartonella infection who had serologic testing performed, all were at least IgG or IgM positive initially or had evidence of a fourfold increase in titers on follow-up testing. The sensitivity of the indirect fluorescence antibody test in immunocompromised patients is lower than in immunocompetent hosts (75% vs. 82-95%). Furthermore, serologic test results can be negative early in the course and may take 2 to 4 weeks to develop. ^, In some cases, patients may never mount a response, even when serology is obtained later in the course. It is important to note that cross-reactions between the different Bartonella species exist, as well as with other zoonoses such as Rickettsiae.

Histologic examination of lymph nodes from affected patients can reveal lymphocytes with epithelioid granulomas, which may later in the course have central zones of necrosis or appear suppurative; some may contain stellate microabscesses. Warthin-Starry or Steiner silver stain demonstrates aggregates of small coccobacilli. This test, however, is not specific for B. henselae . Immunohistochemistry of lymph node tissue with B. henselae –specific antibodies may also reveal evidence of infection.

On biopsy, BA of lymph nodes or skin contains a dense vascular proliferation with plump endothelial cells that protrude into the vascular lumina. There is often a mixed inflammatory infiltrate of both lymphocytes and neutrophils. Biopsies of BP lesions differ from those in BA. Lesions often demonstrate dilated capillaries and cystic blood-filled spaces scattered throughout the hepatic or splenic parenchyma. As do biopsies of lymph nodes in typical CSD, both BA and BP demonstrate clusters of bacilli seen on Warthin-Starry or Steiner silver stain.

Identification of Bartonella in cultures is difficult due to its fastidious growth and culture techniques that are not sensitive. Culturing of Bartonella can require 1 to 4 weeks of incubation on blood agar plates under specific conditions. If culture is performed, specialized laboratories with experience in isolating Bartonella organisms are recommended for processing of cultures.

Polymerase chain reaction (PCR) of DNA extracted from tissue may confirm species identity. PCR assays are available commercially and in research settings for testing of tissue or body fluids, including blood. PCR of tissue has been used to determine the etiology from lymph nodes, hepatosplenic lesions, and lung nodules in immunocompromised hosts. This technique is both sensitive and specific.

Treatment

The need for treatment of CSD in the immuocompetent host is not well established. In the only prospective, randomized trial of treatment of typical CSD in immunocompetent children, there was no clinical difference except in lymph node size at 30 days between those treated with azithromycin versus placebo.

Because severe, progressive, disseminated disease can occur in immunocompromised patients, treatment for Bartonella -associated infections is always recommended in this population. There are no established treatment guidelines for Bartonella infection in transplant recipients. Unlike in immunocompetent hosts, response to treatment is usually prompt in the immunocompromised patient. Pediatric transplant recipients with granulomatous or suppurative disease, including hepatosplenic lesions, have been successfully treated with single agents or combinations of agents: aminoglycosides (gentamicin, amikacin), macrolides (azithromycin, erythromycin), tetracyclines (doxycycline), fluoroquinolones (ciprofloxacin), and trimethoprim-sulfamethoxazole. Durations of therapy have ranged from 2 weeks to 6 months. In most cases, therapy was discontinued when all lymphadenopathy and/or hepatosplenic lesions had resolved. Shorter therapy has been associated with at least one reported recurrence of lymphadenitis in a pediatric kidney transplant recipient.

Azithromycin, doxycycline, and ciprofloxacin have been used successfully in pediatric transplant recipients with BA treated with a 3- to 4- month duration of therapy. In adult SOT recipients, reported length of therapy has ranged from 4 weeks to 6 months, which is similar to reported guidelines for HIV-infected patients with BA. In presumed disseminated CSD and BA or BP, prolonged therapy is generally administered (for at least 3 months and until lesions resolve) with a macrolide antibiotic or tetracycline, either alone or in combination with another efficacious antimicrobial, such as rifampin, an aminoglycoside, or ciprofloxacin. It is important to note, however, that children younger than 8 years in whom a macrolide may be given, doxycycline is not recommended for more than 21 days. Clinicians should also be aware that a Jarisch-Herxheimer reaction may develop after the first few doses of treatment of BA.

Drug-drug interactions must be considered in SOT recipients. Macrolides can increase the serum concentration of some calcineurin inhibitors like tacrolimus, and rifampin is a potent hepatic enzyme inducer and interacts with many drugs.

In addition to antimicrobial therapy, a decrease in immunosuppression is recommended if possible.

Infection prevention and anticipatory guidance

Standard precautions are recommended for children with Bartonella infections.