Case Report
Fever and lymphadenitis in an immunocompromised patient C. Maalouly1, N. Cecere1, D. Wilmes2, N. Demoulin1, J. Morelle1 1
Division of Nephrology, Universite´ catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium, 2Division of Infectious Diseases, Universite´ catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium Objective and importance: Bartonella henselae infections are among the most common causes of fever and lymphadenopathies, but can lead to severe complications in immunocompromised hosts; early recognition of these infections is of paramount importance in immunocompromised patients. Clinical presentation: Here we report the case of a renal transplant recipient who presented with fever, lymphadenopathies, and a splenic abscess secondary to Bartonella henselae infection, successfully treated with doxycycline. Discussion and conclusions: We discuss the various clinical presentations of Bartonella henselae infections in immunocompromised patients and the available diagnostic tools for this potentially severe complication. Keywords: Bartonella henselae, Cat-scratch disease, Lymphadenopathy, Renal transplantation
A 47-year-old man presented with fever, submandibular tumefaction, and supraclavicular lymphadenopathy. Four years before presentation, he underwent kidney transplantation for end-stage renal disease secondary to autosomal dominant polycystic kidney disease. Post-transplantation course was uncomplicated except for early cytomegalovirus reactivation. At the time of presentation, the glucocorticoid-free immunosuppressive regimen included tacrolimus and mycophenolate mofetil, and MDRD-estimated glomerular filtration rate was 56 ml/min/1.73 m2. The patient reported submandibular skin redness 4 weeks before presentation. During the following days, he complained of progressive weakness, night sweats, and vomiting. On physical examination, the patient had an erythematous papular lesion on his right jaw and a firm and painless submandibular swelling on the same side, together with a mobile stiff and sensitive supraclavicular lymph node (Fig. 1A). Temperature was 38.5uC and blood pressure was 120/ 90 mmHg. Laboratory studies revealed increased Creactive protein levels (18 mg/dl) and white blood cell count (13 500/ml), predominantly neutrophilic; platelets were normal, as well as liver enzymes. Blood cultures were negative. Cytomegalovirus and Epstein–Barr virus Correspondence to: J. Morelle, Division of Nephrology, Cliniques universitaires Saint-Luc, Universite´ catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium. Email: [email protected]
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ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000005
polymerase chain reaction (PCR) on the serum, and IgM for toxoplasmosis and human immunodeficiency virus were all negative. Head and neck magnetic resonance imaging was compatible with an abscessed lymph node in the superficial lobe of the parotid. Repeated questioning revealed a history of exposure to cats and the serology for Bartonella henselae (indirect fluorescence assay) was positive, with IgG and IgM levels at 1/320 and .1/100, respectively. PCR by amplification of the rpoB gene on a parotid smear was positive for Bartonella henselae, confirming the diagnosis of cat-scratch disease (CSD). Positron emission tomography/computed tomography scan showed hypermetabolism in the right parotid, in the supraclavicular lymphadenopathy, and in a hypodense lesion of the spleen (Fig. 1A), and reasonably ruled out lymphoproliferative disorders and liver involvement. The patient was started on doxycycline until relief of the symptoms and normalization of the C-reactive protein level. Fever and lymphadenopathy may result from infections, autoimmune disorders, and malignancies. Since supraclavicular lymphadenopathies are the most likely nodes to be malignant, they should always be investigated, especially in solid organ transplant recipients who are at increased risk for post-transplant lymphoproliferative disorders. In immunocompetent hosts, Bartonella henselae infection is usually a self-limited affection known as
Acta Clinica Belgica
2014
VOL.
69
NO.
3
Maalouly et al.
Fever and lymphadenitis in an immunocompromised patient
Figure 1 (A) Skin lesion of the face (arrowhead) and locoregional lymphadenitis (arrow). (B) Fluorodeoxyglucose (FDG) positron emission tomograhy/computed tomography. Increased uptake of 18FDG with maximum standardized uptake values of 5.1, 6.2, and 5.8 indicates hypermetabolism respectively in the right parotid gland, in a right supraclavicular lymph node, and in a spleen nodule.
CSD, characterized by fever and subacute regional lymphadenopathy.1 In addition to that, severelyimmunocompromised patients may develop pathological vasoproliferation in multiple organs, known as bacillary angiomatosis and bacillary peliosis.2 In renal transplant recipients who tend to have less immunosuppression, CSD is the most commonly encountered expression of the disease, but with more severe dissemination2,3 with spleen abscesses reported in some cases.4 History of cat exposure directs towards Bartonella henselae infection. The diagnosis is challenging since culture, Whartin–Starry silver stain, serological testing, and PCR have all their pitfalls.1 Culture of Bartonella species is often difficult and requires 2– 6 weeks of isolation, with a limited sensitivity (13% for CSD, 43% in case of bacillary angiomatosis).7 Several serological tests using indirect fluorescence or enzyme immune-assay have been developed. However, they show a highly variable sensitivity and specificity depending on test procedures, antigen, and cutoff used; other disadvantages of serological tests include their limited capacity to distinguish between active versus prior infection, and potential cross-reactivity between different Bartonella species.8 The availability of PCR assays provides an opportunity for rapid identification with high specificity, although their sensitivity depends on the PCR target and the sample type.8 Careful and complete workup is required, especially in immunocompromised patients who are prone to diffuse organ involvement. DNA PCR by amplification of 16S rRNA gltA or rpoB gene is useful for definitive diagnosis in those
patients and should be performed by experienced laboratories.1 The benefits of antibiotics on the course of CSD in immunocompetent patients is limited and current recommendations for the mild to moderately ill immunocompetent patient is no antibiotic treatment.5 On the contrary, immunocompromised patients with bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis should receive antibiotics; erythromycin and doxycycline have been used successfully and are considered first-line treatment.5,6 Combination therapy using erythromycin or doxycycline with rifampicin is recommended for severe Bartonella infections. Although treatment should be administered for more than 3 months in these conditions, treatment duration of CSD in immunocompromised hosts is not well established. In our patient, CSD was treated with doxycycline alone. Doxycycline was discontinued after a 10-day course, when lymphadenitis had completely vanished, and Creactive protein level was normalized (0.4 mg/dl). The definitive results of the Positron emission tomography/computed tomography scan were obtained after treatment completion. In the context of Bartonella infection, the hypodense and hypermetabolic lesion in the spleen was suggestive of a granuloma, a spleen abscess, or bacillary angiomatosis. However, since bacillary angiomatosis usually manifests on the skin with violaceous lesions mimicking Kaposi sarcoma, and is frequently associated with liver nodules, this diagnosis was considered unlikely in our patient who did not present any cutaneous or hepatic lesion. Formal differential diagnosis between granuloma and
Acta Clinica Belgica
2014
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NO .
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Maalouly et al.
Fever and lymphadenitis in an immunocompromised patient
spleen abscess would have required histological analysis. As patient’s clinical evolution was excellent, antibiotic therapy was not restarted. The patient was closely monitored, but did not experience any recurrence of fever or lymphadenitis during the next 6 months. Eight weeks after the diagnosis, antiBartonella henselae IgG antibodies rose up to 1/1280. Bartonella infections should be included in the list of infections in solid organ transplant patients with fever and lymphadenopathy. Patients should be questioned about cat exposure and, whenever possible, they should be advised to avoid exposure to cats’ scratches, especially kittens. A high index of suspicion in immunocompromised hosts warrants a fast and complete diagnosis workup to stage the disease and promptly initiate the appropriate therapy.
Conflicts of Interest All the authors declared no competing interests.
References 1 Raoult D. From cat scratch disease to Bartonella henselae infection. Clin Infect Dis. 2007;45:1541–2.
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2 Moulin C, Kanitakis J, Ranchin B, Chauvet C, Gillet Y, Morelon E, et al. Cutaneous bacillary angiomatosis in renal transplant recipients: report of three new cases and literature review. Transpl Infect Dis. 2012;14:403–9. 3 Rostad C, McElroy A, Hilinski K, Thompson M, Drew C, Denison A, et al. Bartonella henselae-mediated disease in solid organ transplant recipients: two pediatric cases and a literature review. Transpl Infect Dis. 2012;14:E71–81. 4 Rolain JM, Chanet V, Laurichesse H, Lepidi H, Beytout J, Raoult D. Cat scratch disease with lymphadenitis, vertebral osteomyelitis, and spleen abscesses. Ann NY Acad Sci. 2003;990:397–403. 5 Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother. 2004;48:1921–33. 6 Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIVinfected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58:1–207. 7 La Scola B, Raoult D. Culture of Bartonella quintana and Bartonella henselae from human samples: a 5-year experience (1993 to 1998). J Clin Microbiol. 1999;37:1899–905. 8 Florin T, Zaoutis T, Zaoutis L. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics. 2008;121:e1413–25.
Fever and lymphadenitis in an immunocompromised patient C. Maalouly1, N. Cecere1, D. Wilmes2, N. Demoulin1, J. Morelle1 1
Division of Nephrology, Universite´ catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium, 2Division of Infectious Diseases, Universite´ catholique de Louvain, Cliniques universitaires Saint-Luc, Brussels, Belgium Objective and importance: Bartonella henselae infections are among the most common causes of fever and lymphadenopathies, but can lead to severe complications in immunocompromised hosts; early recognition of these infections is of paramount importance in immunocompromised patients. Clinical presentation: Here we report the case of a renal transplant recipient who presented with fever, lymphadenopathies, and a splenic abscess secondary to Bartonella henselae infection, successfully treated with doxycycline. Discussion and conclusions: We discuss the various clinical presentations of Bartonella henselae infections in immunocompromised patients and the available diagnostic tools for this potentially severe complication. Keywords: Bartonella henselae, Cat-scratch disease, Lymphadenopathy, Renal transplantation
A 47-year-old man presented with fever, submandibular tumefaction, and supraclavicular lymphadenopathy. Four years before presentation, he underwent kidney transplantation for end-stage renal disease secondary to autosomal dominant polycystic kidney disease. Post-transplantation course was uncomplicated except for early cytomegalovirus reactivation. At the time of presentation, the glucocorticoid-free immunosuppressive regimen included tacrolimus and mycophenolate mofetil, and MDRD-estimated glomerular filtration rate was 56 ml/min/1.73 m2. The patient reported submandibular skin redness 4 weeks before presentation. During the following days, he complained of progressive weakness, night sweats, and vomiting. On physical examination, the patient had an erythematous papular lesion on his right jaw and a firm and painless submandibular swelling on the same side, together with a mobile stiff and sensitive supraclavicular lymph node (Fig. 1A). Temperature was 38.5uC and blood pressure was 120/ 90 mmHg. Laboratory studies revealed increased Creactive protein levels (18 mg/dl) and white blood cell count (13 500/ml), predominantly neutrophilic; platelets were normal, as well as liver enzymes. Blood cultures were negative. Cytomegalovirus and Epstein–Barr virus Correspondence to: J. Morelle, Division of Nephrology, Cliniques universitaires Saint-Luc, Universite´ catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium. Email: [email protected]
214
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000005
polymerase chain reaction (PCR) on the serum, and IgM for toxoplasmosis and human immunodeficiency virus were all negative. Head and neck magnetic resonance imaging was compatible with an abscessed lymph node in the superficial lobe of the parotid. Repeated questioning revealed a history of exposure to cats and the serology for Bartonella henselae (indirect fluorescence assay) was positive, with IgG and IgM levels at 1/320 and .1/100, respectively. PCR by amplification of the rpoB gene on a parotid smear was positive for Bartonella henselae, confirming the diagnosis of cat-scratch disease (CSD). Positron emission tomography/computed tomography scan showed hypermetabolism in the right parotid, in the supraclavicular lymphadenopathy, and in a hypodense lesion of the spleen (Fig. 1A), and reasonably ruled out lymphoproliferative disorders and liver involvement. The patient was started on doxycycline until relief of the symptoms and normalization of the C-reactive protein level. Fever and lymphadenopathy may result from infections, autoimmune disorders, and malignancies. Since supraclavicular lymphadenopathies are the most likely nodes to be malignant, they should always be investigated, especially in solid organ transplant recipients who are at increased risk for post-transplant lymphoproliferative disorders. In immunocompetent hosts, Bartonella henselae infection is usually a self-limited affection known as
Acta Clinica Belgica
2014
VOL.
69
NO.
3
Maalouly et al.
Fever and lymphadenitis in an immunocompromised patient
Figure 1 (A) Skin lesion of the face (arrowhead) and locoregional lymphadenitis (arrow). (B) Fluorodeoxyglucose (FDG) positron emission tomograhy/computed tomography. Increased uptake of 18FDG with maximum standardized uptake values of 5.1, 6.2, and 5.8 indicates hypermetabolism respectively in the right parotid gland, in a right supraclavicular lymph node, and in a spleen nodule.
CSD, characterized by fever and subacute regional lymphadenopathy.1 In addition to that, severelyimmunocompromised patients may develop pathological vasoproliferation in multiple organs, known as bacillary angiomatosis and bacillary peliosis.2 In renal transplant recipients who tend to have less immunosuppression, CSD is the most commonly encountered expression of the disease, but with more severe dissemination2,3 with spleen abscesses reported in some cases.4 History of cat exposure directs towards Bartonella henselae infection. The diagnosis is challenging since culture, Whartin–Starry silver stain, serological testing, and PCR have all their pitfalls.1 Culture of Bartonella species is often difficult and requires 2– 6 weeks of isolation, with a limited sensitivity (13% for CSD, 43% in case of bacillary angiomatosis).7 Several serological tests using indirect fluorescence or enzyme immune-assay have been developed. However, they show a highly variable sensitivity and specificity depending on test procedures, antigen, and cutoff used; other disadvantages of serological tests include their limited capacity to distinguish between active versus prior infection, and potential cross-reactivity between different Bartonella species.8 The availability of PCR assays provides an opportunity for rapid identification with high specificity, although their sensitivity depends on the PCR target and the sample type.8 Careful and complete workup is required, especially in immunocompromised patients who are prone to diffuse organ involvement. DNA PCR by amplification of 16S rRNA gltA or rpoB gene is useful for definitive diagnosis in those
patients and should be performed by experienced laboratories.1 The benefits of antibiotics on the course of CSD in immunocompetent patients is limited and current recommendations for the mild to moderately ill immunocompetent patient is no antibiotic treatment.5 On the contrary, immunocompromised patients with bacillary angiomatosis, peliosis hepatis, bacteremia, and osteomyelitis should receive antibiotics; erythromycin and doxycycline have been used successfully and are considered first-line treatment.5,6 Combination therapy using erythromycin or doxycycline with rifampicin is recommended for severe Bartonella infections. Although treatment should be administered for more than 3 months in these conditions, treatment duration of CSD in immunocompromised hosts is not well established. In our patient, CSD was treated with doxycycline alone. Doxycycline was discontinued after a 10-day course, when lymphadenitis had completely vanished, and Creactive protein level was normalized (0.4 mg/dl). The definitive results of the Positron emission tomography/computed tomography scan were obtained after treatment completion. In the context of Bartonella infection, the hypodense and hypermetabolic lesion in the spleen was suggestive of a granuloma, a spleen abscess, or bacillary angiomatosis. However, since bacillary angiomatosis usually manifests on the skin with violaceous lesions mimicking Kaposi sarcoma, and is frequently associated with liver nodules, this diagnosis was considered unlikely in our patient who did not present any cutaneous or hepatic lesion. Formal differential diagnosis between granuloma and
Acta Clinica Belgica
2014
VOL .
69
NO .
3
215
Maalouly et al.
Fever and lymphadenitis in an immunocompromised patient
spleen abscess would have required histological analysis. As patient’s clinical evolution was excellent, antibiotic therapy was not restarted. The patient was closely monitored, but did not experience any recurrence of fever or lymphadenitis during the next 6 months. Eight weeks after the diagnosis, antiBartonella henselae IgG antibodies rose up to 1/1280. Bartonella infections should be included in the list of infections in solid organ transplant patients with fever and lymphadenopathy. Patients should be questioned about cat exposure and, whenever possible, they should be advised to avoid exposure to cats’ scratches, especially kittens. A high index of suspicion in immunocompromised hosts warrants a fast and complete diagnosis workup to stage the disease and promptly initiate the appropriate therapy.
Conflicts of Interest All the authors declared no competing interests.
References 1 Raoult D. From cat scratch disease to Bartonella henselae infection. Clin Infect Dis. 2007;45:1541–2.
216
Acta Clinica Belgica
2014
VOL .
69
NO .
3
2 Moulin C, Kanitakis J, Ranchin B, Chauvet C, Gillet Y, Morelon E, et al. Cutaneous bacillary angiomatosis in renal transplant recipients: report of three new cases and literature review. Transpl Infect Dis. 2012;14:403–9. 3 Rostad C, McElroy A, Hilinski K, Thompson M, Drew C, Denison A, et al. Bartonella henselae-mediated disease in solid organ transplant recipients: two pediatric cases and a literature review. Transpl Infect Dis. 2012;14:E71–81. 4 Rolain JM, Chanet V, Laurichesse H, Lepidi H, Beytout J, Raoult D. Cat scratch disease with lymphadenitis, vertebral osteomyelitis, and spleen abscesses. Ann NY Acad Sci. 2003;990:397–403. 5 Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D. Recommendations for treatment of human infections caused by Bartonella species. Antimicrob Agents Chemother. 2004;48:1921–33. 6 Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H; Centers for Disease Control and Prevention (CDC); National Institutes of Health; HIV Medicine Association of the Infectious Diseases Society of America. Guidelines for prevention and treatment of opportunistic infections in HIVinfected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58:1–207. 7 La Scola B, Raoult D. Culture of Bartonella quintana and Bartonella henselae from human samples: a 5-year experience (1993 to 1998). J Clin Microbiol. 1999;37:1899–905. 8 Florin T, Zaoutis T, Zaoutis L. Beyond cat scratch disease: widening spectrum of Bartonella henselae infection. Pediatrics. 2008;121:e1413–25.
