Matthew J. Dolan

Syndrome of Rochalimaea henselae adenitis suggesting cat scratch disease

Rochalimaea henselae is a causative agent of bacillary angiomatosis [1, 2] and peliosis hepatis [3, 4] in patients infected with human immunodeficiency virus (HIV). The organism has been isolated in culture from both immunocompromised and immunocompetent patients with fever and bacteremia [5, 6]. It has been associated with aseptic meningitis and, like R. quintana and Bartonella spp., can be associated with relapsing disease and with persistent bacteremia in the absence of symptoms [7-12]. Cat scratch disease has been provisionally associated with the fastidious gram-negative rod Afipia felis [13]; however, A. felis has only rarely been isolated from patients with cat scratch disease, and evidence of A. felis-specific antibodies is lacking in most persons with suspected cat scratch disease [14]. In contrast, nearly 90% of persons with suspected cat scratch disease have serologic evidence of Rochalimaea infection [14]. This disease typically presents as adenitis with an evident papular lesion at the inoculation site [15, 16]. Other clinical presentations of cat scratch disease include neurologic syndromes [17], liver disease [18], angiomatous skin lesions [19], and prolonged, recurrent infection [20]. Although several similarities exist between R. henselae infection and cat scratch disease in clinical presentation, the typical cat scratch disease syndrome of adenitis caused by R. henselae has not been described. We report two cases of otherwise healthy patients with upper-extremity adenitis in which R. henselae was isolated from the infected lymph nodes, drawing a parallel to the most common presentation of cat scratch disease and adding to the spectrum of disease caused by R. henselae. Case Reports Patient 1 A 68-year-old white man with a history of mild hypertension was seen in the emergency department; he complained of 72 hours of fever to 39.2 C and an enlarging mass at his left elbow. In the emergency department his temperature was 39.4 C and he had a small eschar in the interphalangeal space of his left hand between the third and fourth digits that he reported had been present for 2 months. His environmental exposures included small lacerations from rose bushes he tended and contact with a pet cat. His leukocyte count was 17.3 109/L with a predominance of neutrophils and band forms. The patient was given a 10-day course of cefadroxil. He became afebrile during therapy but because the left epitrochlear mass was enlarging and becoming painful, he again sought medical attention. At this time he had a small 1 0.5-cm nonhealing ulcer without eschar on the dorsum of the 3 to 4 interphalangeal space of the left hand and a 4 4-cm, tender, nonfluctuant left epitrochlear lymph node. No other adenopathy was present, and the rest of the examination was unremarkable. Laboratory test results, including complete blood count, chemistry profile with liver functions studies, urinalysis, and erythrocyte sedimentation rate, were normal. Result of a test for HIV-1 was negative. A chest roentgenogram was normal. Serologic test results for tularemia, brucellosis, and syphilis were negative. A purified protein-derivative skin test result was negative with positive controls. An excisional biopsy of both the interdigital lesion and the epitrochlear node was done. Histopathologic examination revealed similar processes in both sites characterized by necrotizing granulomas in a background of chronic inflammation, with multinucleated giant cells and a mixed perivascular infiltrate (Figure 1). No organisms were seen with tissue acid fast or Gram stain, Warthin-Starry stain, or Gomori-methenamine-silver stain. Figure 1. Photomicrographs of the papular hand lesion and lymph node of Patient 1. Top left. Top right. Bottom. A sample of the lymph node was cultured, and an organism was isolated that was identified as R. henselae. The patient was treated with a 28-day course of doxycycline and ciprofloxacin. The lesion healed after 10 days, and he has remained symptom free for 9 months. Patient 2 A previously healthy Hispanic 27-year-old man developed a tender left axillary lymph node while traveling through Hawaii, Thailand, Guam, and Bangladesh as a flight crew member. Three days later, he developed fevers to 38.9 C, light-headedness, fatigue, and nausea with one episode of vomiting, chills, diaphoresis, and headache. The systemic symptoms resolved after 3 days, but the node continued to enlarge and became more painful. When we examined him, he was afebrile and complained only of the painful node that limited use of his left arm. The patient owned and handled cats, dogs, and goats and had received tick bites, although not on the affected limb. He had a 4 5-cm nonfluctuant, tender left axillary lymph node with minimal overlying erythema, a 1 1-cm left epitrochlear lymph node that was nontender, and a 1 1-cm eschar on the palmar surface of his left hand. The examination was otherwise unremarkable. Values were normal for a complete blood count, serum chemistry tests, urinalysis, and erythrocyte sedimentation rate. Serologic test results for tularemia, brucellosis, plague, syphilis, and scrub typhus were negative, as was a test for HIV-1. The purified protein derivative skin test was negative with positive controls. An excisional biopsy of the axillary lymph node was done, revealing hard, inflamed, adherent, matted nodes at surgery. The patient was given a 14-day course of cephradine followed by a 28-day course of doxycycline after surgery. Histopathologic examination of the lymph node sample showed findings similar to those of the skin and lymph node biopsies of Patient 1. Cultures of the biopsy material grew rare, small colonies of R. henselae after a prolonged incubation. Concurrent cultures of the blood remained negative after 30 days. The patient recovered and has remained symptom free for 12 months. Methods Microbial Isolation Biopsy material was placed on saline-soaked gauze and carried directly to the microbiology laboratory, where it was ground in a tissue grinder and plated onto chocolate and CDC anaerobic blood agar (sheep blood with added hemin and L-cysteine; BDMS, Cockeysville, Maryland), Jem Bec plates (BDMS) and placed into liquid phase media, including cooked meat broth (BDMS) and eugonic broth (modified, Remel, Lexena, Kansas). Fungal and mycobacterial cultures were also done. These materials were then incubated at 35 C in 5% CO2, with plates kept upright for 24 hours and then inverted. Plates were incubated for up to 6 weeks under these conditions to optimize the isolation of fastidious organisms. For determination of X and V factor dependence, cultures were plated onto brain-heart infusion agar with X, V, and XV strips (BDMS). Broth Microdilution Antimicrobial Susceptibility Tests The two R. henselae isolates described above and a previously described blood isolate [7] were tested for susceptibility to a wide array of antimicrobial agents by a broth microdilution susceptibility method analogous to that used to test Haemophilus influenzae. Specifically, microdilution trays were prepared with twofold concentration increments of the various antimicrobial agents incorporated into Haemophilus test medium [21, 22] dispensed into 100-L/well aliquots. The bacterial inoculum was prepared from growth of the test strains that had been isolated from a single colony and subcultured on enriched chocolate agar and incubated for 5 to 7 days at 35 C in 5% CO2. The final inoculum density used for all susceptibility tests was approximately 5 105 colony-forming units per mL derived by suspending growth in 0.9% NaCl to a turbidity of 0.5 McFarland standard. Plate counts verified the appropriateness of the final inoculum. Microdilution trays were incubated for 7 days at 35 C in ambient air before minimum inhibitory concentrations were interpreted in the usual manner. Whole-Cell Fatty Acid Analysis Analysis of whole-cell fatty acids was done with a Hewlett Packard 5890 gas chromatography system and software (Microbial Identification System, Version 3.0, Microbial ID, Inc., Newark, Delaware). Cultures of R. henselae, R. quintana, and A. felis (strain B.V., Armed Forces Institute of Pathology, Washington, DC) were grown for 7 days on CDC blood agar at 35 C in increased CO2, and then colonies were harvested with a loop. The cellular material was then saponified, methylated, extracted, base-washed, and analyzed as recommended by the manufacturer. DNA Analysis The identification of the bacteria was confirmed by using a combination of the polymerase chain reaction (PCR) amplification of the citrate synthetase gene sequence and subsequent restriction fragment length polymorphism analysis of the resultant amplified DNA product [6, 23]. The PCR-amplified DNA was subjected to restriction-endonuclease digestion with various enzymes (HinfI, HhaI, MseI, and TaqI). The sizes of resulting DNA fragments were compared by polyacrylamide gel electrophoresis with DNA fragments prepared simultaneously from other Rochalimaea strains, including R. quintana (ATCC VR-358, isolate Fuller), R. vinsonii (ATCC VR-152, vole agent), and R. henselae, (Houston-1 prototype isolate). Results Colonies were noted in the area of application on the CDC anaerobic blood plates at day 33 and day 13 in the first and second cases, respectively. Growth was slower on chocolate agar and did not occur on the other media used. Afipia felis (strain B.V.) was subcultured onto blood agar under identical conditions to show that Afipia could be grown using the method described here to isolate R. henselae. Rochalimaea colonies were small, nonhemolytic, rough and dry, and yellow to grey in color. Gram stain revealed small, curved, pleomorphic gram-negative rods. The organism was oxidase and catalase negative and X-factor dependent. Growth occurred more quickly on subsequent subcultures. The most rapid growth was attained using human blood agar. Rochalimaea quintana has previously been shown to grow bet

HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels

Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear phagocytes (MP) in the pathogenesis of HIV-associated dementia (HAD). We determined the influence of genetic variation in MCP-1 on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for the MCP-1 –2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this same MCP-1 genotype was associated with accelerated disease progression and a 4.5-fold increased risk of HAD. We examined the molecular and cellular basis for these genotype–phenotype associations and found that the mutant MCP-1 –2578G allele conferred greater transcriptional activity via differential DNA–protein interactions, enhanced protein production in vitro, increased serum MCP-1 levels, as well as MP infiltration into tissues. Thus, MCP-1 expression had a two-edged role in HIV-1 infection: it afforded partial protection from viral infection, but during infection, its proinflammatory properties and ability to up-regulate HIV-1 replication collectively may contribute to accelerated disease progression and increased risk of dementia. Our findings suggest that MCP-1 antagonists may be useful in HIV-1 infection, especially for HAD, and that HIV+ individuals possessing the MCP-1 –2578G allele may benefit from early initiation of antiretroviral drugs that effectively cross the blood–brain barrier. In a broader context, the MCP-1 –2578G allele may serve as a genetic determinant of outcome of other disease states in which MP-mediated tissue injury is central to disease pathogenesis.

Global survey of genetic variation in CCR5, RANTES, and MIP-1α: Impact on the epidemiology of the HIV-1 pandemic

Expression of CC chemokine receptor 5 (CCR5), the major coreceptor for HIV-1 cell entry, and its ligands (e.g., RANTES and MIP-1α) is widely regarded as central to the pathogenesis of HIV-1 infection. By surveying nearly 3,000 HIV+ and HIV− individuals from worldwide populations for polymorphisms in the genes encoding RANTES, MIP-1α, and CCR5, we show that the evolutionary histories of human populations have had a significant impact on the distribution of variation in these genes, and that this may be responsible, in part, for the heterogeneous nature of the epidemiology of the HIV-1 pandemic. The varied distribution of RANTES haplotypes (AC, GC, and AG) associated with population-specific HIV-1 transmission- and disease-modifying effects is a striking example. Homozygosity for the AC haplotype was associated with an increased risk of acquiring HIV-1 as well as accelerated disease progression in European Americans, but not in African Americans. Yet, the prevalence of the ancestral AC haplotype is high in individuals of African origin, but substantially lower in non-Africans. In a Japanese cohort, AG-containing RANTES haplotype pairs were associated with a delay in disease progression; however, we now show that their contribution to HIV-1 pathogenesis and epidemiology in other parts of the world is negligible because the AG haplotype is infrequent in non-Far East Asians. Thus, the varied distribution of RANTES, MIP-1α, and CCR5 haplotype pairs and their population-specific phenotypic effects on HIV-1 susceptibility and disease progression results in a complex pattern of biological determinants of HIV-1 epidemiology. These findings have important implications for the design, assessment, and implementation of effective HIV-1 intervention and prevention strategies.

Clinical Outcomes of Elite Controllers, Viremic Controllers, and Long-Term Nonprogressors in the US Department of Defense HIV Natural History Study

Durable control of human immunodeficiency virus (HIV) replication and lack of disease progression in the absence of antiretroviral therapy were studied in a military cohort of 4586 subjects. We examined groups of elite controllers (ie, subjects with plasma HIV RNA levels of <50 copies/mL; prevalence, 0.55% [95% confidence interval {CI}, 0.35%-0.80%]), viremic controllers (ie, subjects with plasma HIV RNA levels of 50-2000 copies/mL; prevalence, 3.34% [95% CI, 2.83%-3.91%]), and subjects with a lack of disease progression (ie, long-term nonprogressors [LTNPs]) through 7 years of follow-up (LTNP7s; prevalence, 3.32% [95% CI, 2.70%-4.01%]) or 10 years of follow-up (LTNP10s; prevalence, 2.04% [95% CI, 1.52%-2.68%]). For elite and viremic controllers, spontaneous virologic control was established early and was typically observed when the initial viral load measurement was obtained within 1 year of estimated seroconversion. Elite controllers had favorable time to development of AIDS (P=.048), a CD4 cell count of 350 cells/microL (P= .009), and more-stable CD4 cell trends, compared with viremic controllers. LTNPs defined by 10-year versus 7-year criteria had a longer survival time (P=.001), even after adjustment for differing periods of invulnerability (P= .042). Definitions of controllers and LTNPs describe distinct populations whose differing clinical outcomes improve with the stringency of criteria, underscoring the need for comparability between study populations.

Bartonella henselae neuroretinitis in cat scratch disease : Diagnosis, management, and sequelae

OBJECTIVE This study aimed to report the long-term outcomes of patients treated with an antibiotic drug combination for Bartonella henselae neuroretinitis. DESIGN The study design was a retrospective case series. PARTICIPANTS Seven consecutive patients with neuroretinitis and cat scratch disease participated. INTERVENTIONS Patients underwent medical and ophthalmic evaluations. Blood cultures were obtained, and B. henselae antibody titers were measured. Tuberculosis, Lyme, toxoplasmosis, syphilis, and sarcoidosis were excluded. Patients received oral doxycycline 100 mg and rifampin 300 mg twice daily for 4 to 6 weeks and were observed for an average of 16 months (range, 10-24 months). Formal electrophysiologic testing was performed in three patients after resolution of neuroretinitis. MAIN OUTCOME MEASURES The changes in ocular inflammation and visual function associated with treatment were recorded. Follow-up examinations and electrophysiologic testing documented sequelae. RESULTS Patients presented following cat exposure with fever, malaise, and blurred vision. Decreased visual acuity (ranging from 20/40 to counting fingers) frequently was associated with dyschromatopsia and afferent pupillary defects. Ophthalmoscopic analysis showed signs of neuroretinitis, including nerve fiber layer hemorrhages, cotton-wool spots, multiple discrete lesions in the deep retina, and stellate macular exudates. B. henselae infection was confirmed with positive blood cultures or elevated immunofluorescent antibody titers or both. Therapy appeared to promote resolution of neuroretinitis, restoration of visual acuity, and clearance of bacteremia. After 1 to 2 years, two eyes had residual disc pallor, afferent pupillary defects, retinal pigmentary changes, and mildly decreased visual acuity. Electrophysiologic studies showed that when compared to the fellow eye, affected eyes had subnormal contrast sensitivity, abnormal color vision, and abnormal visually evoked potentials. Conversely, electroretinograms were normal in all subjects. CONCLUSIONS B. henselae is a cause of neuroretinitis in cat scratch disease. Compared to historic cases, doxycycline and rifampin appeared to shorten the course of disease and hasten visual recovery. Long-term prognosis is good, but some individuals may acquire a mild postinfectious optic neuropathy.

CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry–independent mechanisms.

Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC -46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC -46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, approximately 11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.

Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression

Originally recognized for their role in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E isoforms (apoE2, apoE3, and apoE4) have also been implicated to play a key role in several biological processes not directly related to their lipid transport function. For example, apoE4 contributes significantly to neurodegeneration in Alzheimers disease. However, the role of apoE in infectious diseases is less well defined. Here, by examining a large cohort of HIV+ European and African American subjects, we found that the APOE ε4/ε4 genotype is associated with an accelerated disease course and especially progression to death compared with the APOE ε3/ε3 genotype. However, an association between the ε4/ε4 genotype and HIV-associated dementia (HAD), a neurological condition with clinicopathological features similar to Alzheimers disease, was not detected. Consistent with the genotype–phenotype relationships observed, compared with recombinant apoE3, apoE4 enhanced HIV fusion/cell entry of both R5 and X4 HIV strains in vitro. These findings establish apoE as a determinant of HIV-AIDS pathogenesis and raise the possibility that current efforts to convert apoE4 to an “apoE3-like” molecule to treat Alzheimers disease might also have clinical applicability in HIV disease.

Pneumonia associated with near-drowning

Drowning and near-drowning can abruptly devastate the lives of both the affected victims and their families. In addition to the complications directly caused by the submersion, several indirect causes of morbidity exist. Infection is one of the complications associated with near-drowning, and pneumonia is the most severe of these infectious complications. The risk factors, microbiological causes, diagnostic approach, and appropriate therapy for pneumonia associated with near-drowning are not well described in the literature. Herein, we review the epidemiology and pathophysiology associated with near-drowning, discuss the potential mechanisms of infection, and describe the likely risk factors for pneumonia related to near-drowning. We also detail the microbiological causes of this entity and provide important clinical and epidemiological information associated with specific pathogens. Finally, we summarize an appropriate diagnostic and therapeutic approach to pneumonia associated with near-drowning.

CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals

The basis for the extensive variability seen in the reconstitution of CD4+ T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4+ T cells/mm3. The CCL3L1-CCR5 genotypes favoring CD4+ T cell recovery are similar to those that blunted CD4+ T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4+ cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.