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Case 5: 10-Year-Old Girl with Fever, Cutaneous Nodules, and Anemia
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Patient Presentation
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History
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Physical Exam
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Differential Diagnosis
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Diagnostic Workup and Initial Clinical Course
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Discussion
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Subsequent Clinical Course: Resolution
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References
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Figures
Figure 1.Pedunculated nodules on skin surface
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Figure 2.Nodules of various sizes on the face
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Figure 3.Nodules around mouth and lesion on tongue
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Figure 4.Skin lesions on face 4 weeks after treatment
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Patient Presentation
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A 10-year-old girl with HIV infection presented to an HIV treatment facility in Lusaka, Zambia, with fever, rash, and weight loss.

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History
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The patient is a 10-year-old Zambian girl who was brought by an aunt to the clinic in January 2006 for evaluation to begin antiretroviral therapy (ART). She is believed to have been infected with HIV congenitally, and was diagnosed at a private clinic in another town with a baseline CD4 count of 89 cells/µL (CD4 percentage: 19%). Her past medical history was otherwise notable for growth retardation, recurrent pneumonia, and pulmonary tuberculosis. She had no known drug allergies.

At her initial antiretroviral (ARV) clinic visit, she reported chronic diarrhea, painful feet, and subjective fevers. On examination, she was afebrile and her weight (18 kg) was low for her age. Her physical examination was significant for a fine papular pruritic rash, conjunctival pallor, crackles at the left lung base, and a soft but distended abdomen. Results of laboratory tests performed at that time included a hemoglobin level of 8.1 g/dL, white blood cell (WBC) count of 5,800 cells/µL, and platelet count of 409,000 cells/µL. She was prescribed trimethoprim-sulfamethoxazole (TMP-SMX, cotrimoxazole) as prophylaxis against Pneumocystis jiroveci pneumonia, mebendazole as empiric treatment of her diarrhea (to cover helminthic infections such as Strongyloides stercoralis), hydrocortisone ointment to suppress her rash, as well as multivitamins, vitamin B6, and folic acid as nutritional supplements.

She returned to the clinic 3 weeks later, reporting resolution of the diarrhea and the subjective fevers. She had gained 2 kg, but still had a pruritic rash that then was treated with a 2% sulfur ointment. She had not yet started the TMP-SMX regimen, but was instructed to do so and to return in 2 weeks for initiation of ART. At her clinic visit 2 weeks later, ARV initiation was postponed because of delays in obtaining laboratory results and the unavailability of her caregiver. By now she had begun the TMP-SMX regimen, and continued on this regimen. During the subsequent 6 weeks, her clinical status continued to improve and she maintained a stable weight. However, during a visit at the end of February, she complained of continued pruritic rash and recurrence of fevers and diarrhea. Records of treatment rendered at that visit are unavailable. A complete blood count (CBC) was requested. At a return visit in mid-March, she again reported improvement in the rash, and also the diarrhea. Fever was not noted in the chart. At this time, CBC results from her previous visit were available:

  • WBC count: 3,500 cells/µL

  • Hemoglobin level: 4.4 g/dL

  • Hematocrit: 14.7%

Additional laboratory results drawn at the patient's mid-March visit revealed:

  • WBC count: 5,700 cells/µL

  • Hemoglobin level: 6.8 g/dL

  • Platelet count: 832,000 cells/µL

  • CD4 count: 141 cells/µL (CD4 percentage: 7.3%)

  • Alanine aminotransferase (ALT) level: 17 IU/L

  • Aspartate aminotransferase (AST) level: 37 IU/L

  • Creatinine level: 20 mg/dL

ARV initiation again was postponed. The reasons for ART deferral during this period are not entirely clear, but appear to be based on a combination of factors, including delays in obtaining the patient's laboratory results and concerns that she had an underlying opportunistic infection (OI) that required diagnosis and treatment before ART initiation. The clinic treatment protocol defers ART initiation in patients with signs or symptoms of an active OI.

When the patient returned to the clinic in early April, she was afebrile and deemed clinically stable, so an ART regimen consisting of nevirapine, lamivudine, and stavudine was initiated. At that visit, her examination was notable for small (0.5 cm in diameter) papules on her face. Documentation in the patient's chart does not indicate clearly whether this was a new rash, or whether she had other symptoms. A presumptive diagnosis of molluscum contagiosum was made.

She returned approximately 3 weeks later complaining of painful and pruritic nodules that had developed soon after she started ART, subjective fever, generalized weakness, and body aches.

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Physical Exam
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  • General: Ill-appearing child, alert and oriented

  • Vital signs: Temperature--40ºC; blood pressure--126/77 mmHg; pulse--120 beats per minute

  • Skin: Diffusely scattered pedunculated nodules of various sizes up to 1.5 cm in diameter, red to violaceous in color, some with vascular quality; these were most prominent on the face, around the eyes, and on the forehead, but were also present on her trunk, abdomen, back, and extremities (upper more than lower). A collarette of scale was noted on some of the lesions (see Figure 1, Figure 2, Figure 3).

  • Head: Normal conjunctiva; rare erythematous nodules on the buccal mucosa, tongue, and external ear canals

  • Neck: No lymphadenopathy

  • Heart: Tachycardia with 1/6 flow murmur

  • Chest: Lungs clear to auscultation bilaterally

  • Abdomen: Flat, soft, diffusely tender to palpation; no hepatosplenomegaly. Multiple cutaneous nodules similar to those elsewhere (see Skin); also tender subcutaneous nodules which were immobile and fixed to the abdominal wall musculature.

  • Extremities: No edema, and unremarkable except for dermatologic lesions.

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Differential Diagnosis
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Kaposi sarcoma

Bacillary angiomatosis

Disseminated cryptococcosis or other disseminated fungal disease

Molluscum contagiosum

Immune reconstitution inflammatory syndrome in a patient who recently initiated ART

Pyogenic granuloma

Angiosarcoma

Mycobacterium marinum or other atypical mycobacteria

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Diagnostic Workup and Initial Clinical Course
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The patient was referred to the regional hospital, where she was admitted with a tentative diagnosis of Kaposi sarcoma and fever of unknown source. A workup of her fever was undertaken. Test results for serum cryptococcal antigen were negative, and the results of 3 sputum smears for acid-fast bacilli also were negative. A blood smear for malaria was negative. Blood cultures were negative. No biopsy was available.

The patient was treated with penicillin and chloramphenicol for fever of unknown origin, to include coverage coverage for meningoccocus. She remained febrile; however, no new skin lesions appeared after hospital admission. She continued receiving TMP-SMX and ART. She was given a transfusion for severe anemia, after which her hemoglobin level rose to 8.8 g/dL.

Several days into the hospital stay, digital photographs (see Figure 1, Figure 2, Figure 3) were obtained and a consultation via the Internet with an HIV-experienced dermatologist was requested.

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Discussion
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This case of a 10-year-old child with high fever, malaise, myalgia, abdominal pain, profuse skin lesions, and severe anemia is illustrative of both the limitations and opportunities encountered in addressing diagnostic dilemmas in resource-constrained settings. The patient typically was seen by a different clinician on each clinic visit, and documentation of the clinical evaluation often was incomplete. Laboratory investigations were limited to the most common causes of fever and systemic disease in HIV-infected persons in this region, ie, cryptococcal infection, tuberculosis, and malaria. Unfortunately, biopsy was not available and, ultimately, the diagnosis was presumptive, rather than histologic.

The most common cause of vascular skin lesions in Zambia is Kaposi sarcoma, and an initial consideration in this case was the possibility that the skin lesions and the systemic febrile illness were unrelated. That is, the girl may have had Kaposi sarcoma as well as acute malaria or tuberculosis. However, these skin lesions were not characteristic of endemic Kaposi sarcoma for a number of reasons: they were all pedunculated nodules without associated lymphedema, many of them had a collarette of scale, and they were associated with fever and abdominal symptoms. Although the initial lesions reportedly were consistent with molluscum contagiosum, this viral infection does not cause vascular lesions with fever. Disseminated infection with Cryptococcus neoformans is an important consideration in an HIV-infected patient with fever and a nodular rash. Cryptococcal disease is a common cause of mortality in this region. However, disseminated cryptococcal disease would be expected to reveal signs and symptoms of meningeal involvement, which were not prominent in this patient. In addition, cryptococcal lesions are flesh-colored or pink and are not vascular. This patient tested negative for serum cryptococcal antigen; unfortunately, cerebrospinal fluid examination was not available. Finally, the rapid proliferation of skin lesions in the weeks immediately following introduction of ART raises the possibility of an immune reconstitution inflammatory syndrome (IRIS).

The consultants and primary physician in this case felt that these highly vascular, inflammatory, discrete skin lesions were characteristic of infection with Bartonella species. In an immunocompetent host, Bartonella infections comprise Bartonella quintana, manifesting as trench fever, Bartonella henselae, which causes catscratch disease, and Bartonella bacilliformis, which causes Oroya fever (Carrión disease) and verruga peruana complex. Among HIV-infected individuals, the most commonly reported manifestations are associated with B henselae and B quintana, and include bacillary angiomatosis and visceral peliosis (peliosis hepatis or splenis). Other species, such as Bartonella clarridgeiae, may cause infection in cats.

This patient's clinical syndrome is consistent with B henselae infection. In HIV-infected patients, bacillary angiomatosis most commonly presents with fever and variable numbers of erythematous, vascularized, cutaneous and subcutaneous papules, which may enlarge into pedunculated, violaceous lesions that bleed easily. Patients with hepatic and splenic peliosis present with fever of 2-8 weeks' duration, abdominal pain, tender organomegaly, and elevated hepatic transaminases.(1) They also may have myalgias and arthralgias. Notably, fever and/or skin lesions may be present for many months before diagnosis.(2) Pancytopenia may occur, as a complication of splenic sequestration or direct invasion of bone marrow by B henselae. However, B henselae is not believed to bind to intact human erythrocytes in the same way that B bacilliformis does; thus, hemolytic anemia is not seen in B henselae infection.(3) In rarer cases, infection may involve the gastrointestinal and respiratory tracts, bone, or central nervous system.

This patient's presentation also resembles Oroya fever (Carrión disease) and verruga peruana. Oroya fever refers to the acute phase of infection with B bacilliformis, as described in immunocompetent adults in South America. Symptoms include fever, myalgia, headache, lymphadenopathy, and hemolytic anemia, beginning approximately 2-16 weeks after being bitten by the sandfly vector Lutzomyia verrucarum. The chronic phase of infection, verruga peruana, may or may not be preceded by Oroya fever, and is heralded by the onset of multiple skin lesions and musculoskeletal pain. Lesions may begin as discrete, reddish, warty papules of approximately 0.2 cm in diameter, often appearing first on the face and extremities. They progress to larger (approximately 4 cm in diameter) grapelike nodules that are highly vascular and may rupture, ulcerate, or bleed. The mouth, esophagus, and linings of the gastrointestinal tract, urinary bladder, uterus, and vagina may become involved. In some cases seizures may occur.(4)

Although classic verruga peruana originally was thought to be limited to Peru, Ecuador, and Columbia, a larger geographic distribution has been hypothesized.(5) It is unknown whether other Lutzomyia species transmit B bacilliformis; however, data on previously known and 12 newly described species and subspecies of Bartonella have emerged in recent years, and the full spectrum of Bartonella infection probably is not known.(6) Whereas the prevalence of Bartonella-associated disease in HIV-infected patients in sub-Saharan Africa is unknown, B henselae infection has been well documented in HIV-infected patients in South Africa, and has been found in domestic cats in South Africa and Zimbabwe and in lions and cheetahs in South Africa.(7-10) Evidence of B henselae and B clarridgeiae has been described in dogs in Zimbabwe and Gabon.(11,12)

Antibiotic treatment of Bartonella infections generally is successful in curing the disease. Drugs that have been shown to be effective for treatment of B henselae and B quintana include azithromycin, clarithromycin, erythromycin, doxycycline, minocycline, and tetracycline. Penicillins and cephalosporins have not been shown to be effective against B henselae and B quintana. Gentamicin or rifampin may be effective; it is not clear whether TMP-SMX and fluoroquinolones are adequate treatments. B bacilliformis strains are highly susceptible in vitro to most beta-lactams, aminoglycosides, macrolides, doxycycline, and rifampin. For treatment of Oroya fever, chloramphenicol has been the most widely used agent, with or without penicillin G. Streptomycin, erythromycin, and tetracycline are alternatives. Patients with verruga peruana may be treated with rifampin, ciprofloxacin, azithromycin, or erythromycin.(13-15) Treatment should be given for 8-12 weeks.

Bartonella infection in this patient with advanced HIV disease cannot be confirmed, given the limited diagnostic tools available in this clinical setting in Zambia. However, this diagnosis is consistent with many aspects of her presentation, including the fever, severe anemia, and vascular skin lesions. At the time of her hospitalization, the patient was treated with chloramphenicol for fever of unknown source. Fortuitously, chloramphenicol has activity against most, if not all, Bartonella species, and the patient's clinical status improved. Thus, her clinical presentation, characteristic skin lesions, and response to therapy are highly supportive of a diagnosis of Bartonella infection, most likely with B henselae.

A final consideration in this case is the relatively abrupt worsening of the patient's constitutional symptoms and the cutaneous eruptions coincident with her initiating ART. This timing suggests possible involvement of an immune reconstitution inflammatory syndrome. The de novo appearance of skin lesions from Bartonella infection after the introduction of ART has not been reported, though there have been anecdotal cases of worsening skin lesions subsequent to ART initiation.(16) It is unknown whether ARV-mediated immune restoration contributed to the patient's symptoms.

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Subsequent Clinical Course: Resolution
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After 1 week of treatment with chloramphenicol and penicillin, the patient defervesced, the myalgia and arthralgias improved, and the patient noted increased energy and sense of well-being. No new skin lesions appeared. During this time, with the assistance of an HIV-experienced dermatologist who was consulted via the Internet, the presumptive diagnosis of Bartonella infection was made.

Upon discharge from the hospital, the patient was given erythromycin in place of chloramphenicol, for treatment of Bartonella infection. She continued erythromycin treatment and returned 4 weeks later, reporting complete resolution of symptoms and substantial decrease in size and number of skin lesions. (See Figure 4.)

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References

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1.   Koehler JE. Bartonella-associated infections in HIV-infected patients. AIDS Clin Care 1995; 7:97-102.
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2.   Koehler JE, Quinn FD, Berger TG, LeBoit PE, Tappero JW. Isolation of Rochalimaea species from cutaneous and osseous lesions of bacillary angiomatosis. N Engl J Med 1992; 327:1625-31.
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3.  Edwards B, Hinthorn D. Bartonellosis. eMedicine; New York: WebMD; 2006. Available at: http://www.emedicine.com/med/topic212.htm. Accessed September 28, 2006.
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4.  Scott G. Bartonellosis. In: Cook GC, ed. Manson's Tropical Diseases. London: WB Sanders Company; 1996:895-896.
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5.  Marr JS. Bartonellosis: Inter-American Institute for Advanced Studies in Cultural History; 2000.
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6.   Pretorius AM, Kelly PJ. An update on human bartonelloses. Cent Afr J Med 2000; 46:194-200.
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7.   Frean J, Arndt S, Spencer D. High rate of Bartonella henselae infection in HIV-positive outpatients in Johannesburg, South Africa. Trans R Soc Trop Med Hyg 2002; 96:549-50.
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8.   Kelly PJ, Matthewman LA, Hayter D, Downey S, Wray K, Bryson NR, Raoult D. Bartonella (Rochalimaea) henselae in southern Africa--evidence for infections in domestic cats and implications for veterinarians. J S Afr Vet Assoc 1996; 67:182-7.
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9.   Pretorius AM, Kuyl JM, Isherwood DR, Birtles RJ. Bartonella henselae in African lion, South Africa. Emerg Infect Dis 2004; 10:2257-8.
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10.   Molia S, Chomel BB, Kasten RW, Leutenegger CM, Steele BR, Marker L, Martenson JS, Keet DF, Bengis RG, Peterson RP, Munson L, O'Brien SJ. Prevalence of Bartonella infection in wild African lions (Panthera leo) and cheetahs (Acinonyx jubatus). Vet Microbiol 2004; 100:31-41.
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11.   Gundi VA, Bourry O, Davous B, Raoult D, La Scola B. Bartonella clarridgeiae and B. henselae in dogs, Gabon. Emerg Infect Dis 2004; 10:2261-2.
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12.   Kelly PJ, Eoghain GN, Raoult D. Antibodies reactive with Bartonella henselae and Ehrlichia canis in dogs from the communal lands of Zimbabwe. J S Afr Vet Assoc 2004; 75:116-20.
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13.  Koehler JE. HIV and Bartonella: Bacillary Angiomatosis and Peliosis. In: Peiperl L, Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [textbook online]. San Francisco: UCSF Center for HIV Information; 1997. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-05-01-03. Accessed September 28, 2006.
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14.   Huarcaya E, Maguina C, Torres R, Rupay J, Fuentes L. Bartonelosis (Carrion's Disease) in the pediatric population of Peru: an overview and update. Braz J Infect Dis 2004; 8:331-9.
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15.   Bass JW, Freitas BC, Freitas AD, Sisler CL, Chan DS, Vincent JM, Person DA, Claybaugh JR, Wittler RR, Weisse ME, Regnery RL, Slater LN. Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease. Pediatr Infect Dis J 1998; 17:447-52.
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16.  Koehler, JE. Personal communication, October 2006.
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