Michael T. Melia

Racial Differences in Hepatitis C Treatment Eligibility

Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG‐IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self‐reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46‐1.87; P < 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001). Conclusion: Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency. (HEPATOLOGY 2011;)

Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system

Objective: To determine the feasibility of next-generation sequencing (NGS) microbiome approaches in the diagnosis of infectious disorders in brain or spinal cord biopsies in patients with suspected CNS infections. Methods: In a prospective pilot study, we applied NGS in combination with a new computational analysis pipeline to detect the presence of pathogenic microbes in brain or spinal cord biopsies from 10 patients with neurologic problems indicating possible infection but for whom conventional clinical and microbiology studies yielded negative or inconclusive results. Results: Direct DNA and RNA sequencing of brain tissue biopsies generated 8.3 million to 29.1 million sequence reads per sample, which successfully identified with high confidence the infectious agent in 3 patients for whom validation techniques confirmed the pathogens identified by NGS. Although NGS was unable to identify with precision infectious agents in the remaining cases, it contributed to the understanding of neuropathologic processes in 5 others, demonstrating the power of large-scale unbiased sequencing as a novel diagnostic tool. Clinical outcomes were consistent with the findings yielded by NGS on the presence or absence of an infectious pathogenic process in 8 of 10 cases, and were noncontributory in the remaining 2. Conclusions: NGS-guided metagenomic studies of brain, spinal cord, or meningeal biopsies offer the possibility for dramatic improvements in our ability to detect (or rule out) a wide range of CNS pathogens, with potential benefits in speed, sensitivity, and cost. NGS-based microbiome approaches present a major new opportunity to investigate the potential role of infectious pathogens in the pathogenesis of neuroinflammatory disorders.

The First US Domestic Report of Disseminated Mycobacterium avium Complex and Anti-Interferon-γ Autoantibodies

IntroductionAnti-interferon-γ (IFNγ) autoantibodies have been associated with disseminated mycobacterial infections, mostly in patients from Southeast Asia.PurposeWe studied an American-born, Caucasian female with M. avium complex infection of the subglottic mucosa and brain for underlying etiologies of infection.MethodsPlasma was screened for anticytokine autoantibodies using a Luminex-based approach. The ability of patient plasma to block IFNγ-induced STAT1 phosphorylation in normal blood cells was evaluated by flow cytometry with intracellular staining. Plasma inhibition of IFNγ production and IFNγ-induced cytokines in normal and patient blood cells washed of autologous plasma was also evaluated.ResultsPatient plasma contained high-titer IgG anti-IFNγ autoantibodies, primarily of the IgG1 subclass. Patient but not control plasma prevented IFNγ-induced STAT1 phosphorylation and expression of the IFNγ-inducible cytokines tumor necrosis factor (TNF) α and interleukin (IL)-12 in normal blood cells. Patient blood cells washed free of autologous plasma demonstrated normal IFNγ production and response.ConclusionsDisseminated nontuberculous mycobacterial infections should always prompt immune evaluation. This first case of disseminated nontuberculous mycobacterial infection and anti-IFNγ autoantibodies in an American-born Caucasian suggests that anti-cytokine autoantibodies are not racially or regionally restricted.

Characteristics and Treatment Outcomes of Propionibacterium acnes Prosthetic Shoulder Infections in Adults

P. acnes shoulder prosthetic joint infections were predominantly characterized by pain and functional loss. Inflammatory marker elevation occurred in just under 50% of cases. Isolates were broadly susceptible to guideline concordant antimicrobials. Antibiotic-only and combined antibiotic-surgical intervention outcomes were similar.

Misdiagnosis of Late-Onset Lyme Arthritis by Inappropriate Use of Borrelia burgdorferi Immunoblot Testing with Synovial Fluid

ABSTRACT The primary objective of this study was to determine whether patients with putative late-onset Lyme arthritis based upon synovial fluid Borrelia burgdorferi IgM and IgG immunoblot testing offered by commercial laboratories satisfied conventional criteria for the diagnosis of Lyme arthritis. Secondary objectives included assessing the prior duration and responsiveness of associated antibiotic therapy. We conducted a retrospective analysis of 11 patients referred to an academic medical center infectious disease clinic during the years 2007 to 2009 with a diagnosis of Lyme disease based upon previously obtained synovial fluid B. burgdorferi immunoblot testing. Ten of the 11 (91%) patients with a diagnosis of late-onset Lyme arthritis based upon interpretation of synovial fluid B. burgdorferi immunoblot testing were seronegative and did not satisfy published criteria for the diagnosis of late-onset Lyme arthritis. None of the 10 patients had a clinical response to previously received antibiotics despite an average course of 72 days. Diagnosis of Lyme arthritis should not be based on synovial fluid B. burgdorferi immunoblot testing. This unvalidated test does not appear useful for the diagnosis of Lyme disease, and this study reinforces the longstanding recommendation to use B. burgdorferi immunoblot testing only on serum samples and not other body fluids. Erroneous interpretations of “positive” synovial fluid immunoblots may lead to inappropriate antibiotic courses and delays in diagnosis of other joint diseases.

Mycotic aortic aneurysm due to intravesical BCG immunotherapy: Clinical manifestations and diagnostic challenges.

A live, attenuated form of Mycobacterium bovis, bacillus Calmette-Guérin (BCG), is commonly used as intravesical immunotherapy for non-invasive urothelial bladder carcinoma. While complications are rare, dissemination can occur. A case of mycotic aortic aneurysm following BCG administration with recovery of Mycobacterium bovis in culture is reported. A review of the published experience with this problem is also presented.

Lyme Disease: Authentic Imitator or Wishful Imitation?

The spirochete Borrelia burgdorferi may afflict skin, heart, joints, and the central or peripheral nervous system. This agent of Lyme disease, perhaps because of its varied presentations, is often raised as the cause of headache, fatigue, and subjective neurocognitive dysfunction. For clinicians who trained in the 20th century when the spirochete Treponema pallidum was invoked as the “Great Imitator,” testing for Lyme disease now seems as or more common than it had been for syphilis. With a narrower disease spectrum than syphilis, is such frequent testing for Lyme disease justified, and how should results be interpreted? If contemplating Lyme neuroborreliosis, understanding the epidemiologic likelihood of acquiring this tick-borne infection, its potential manifestations, and proper interpretation of serologic testing are all essential. For patients from Lyme-endemic areas, Lyme disease is among the most common causes of facial nerve palsy, aseptic meningitis, and neuroradiculitis. While such manifestations of early disseminated Lyme disease arise in up to 10% to 15% of patients not treated at an earlier stage, late neurologic complications such as encephalitis and diffuse polyneuropathy are exceptionally rare. Despite the rarity of late Lyme neuroborreliosis, many physicians include Lyme disease in their differential diagnosis for a variety of chronic neurologic syndromes. This approach may be partly because of brain imaging reports that commonly reference Lyme disease among the possible explanations for nonspecific white matter changes, despite the fact that B burgdorferi infection essentially never causes such findings.1 B burgdorferi infection is well known to affect the seventh and less commonly sixth cranial nerves. An often-posed question, therefore, is whether B burgdorferi infection can produce other isolated cranial neuropathies, such as sensorineural hearing loss and optic neuritis. A recent review advocated against screening patients with sudden-onset sensorineural hearing loss for Lyme disease because of an unproven causative relationship.2 While children with Lyme meningitis can have papilledema, and adults with B burgdorferi–driven optic neuritis manifesting as papillitis have been described, this latter phenomenon appears uncommon. A case series of 440 patients with optic neuritis from a Lyme-endemic region found 25 seropositive but only 1 with evidence of active B burgdorferi infection.3 The rarity of this association was reinforced in the accompanying literature review. Lyme disease is often investigated during the initial evaluation of conditions such as multiple sclerosis, amyotrophic lateral sclerosis, dementia, or parkinsonism. Many patients facing these devastating diseases maintain hope for a curable diagnosis, such as Lyme disease; this optimism is bolstered by Internet resources supporting such notions. A critical point, however, is the highly focal geographic distribution of Lyme disease—none of the aforementioned neurologic diseases are unique to areas with high Lyme disease transmission. Furthermore, Lyme disease is readily distinguished from these conditions on clinical grounds. Patients with Lyme disease do not exhibit the white matter plaques seen on imaging of patients with multiple sclerosis, for example, and when patients with Lyme disease have oligoclonal bands in their cerebrospinal fluid, they are actually reactive against B burgdorferi. Lyme disease does not produce the upper motor neuron signs seen in amyotrophic lateral sclerosis.4 While sometimes considered as an explanation for objective neuropathology, more often asked is if Lyme disease explains subjective neurocognitive dysfunction. Such inquiries likely stem from early reports of neurocognitive symptoms accompanying objective, inflammatory manifestations of Lyme disease, including Lyme arthritis.1 While such symptoms can be seen with Lyme disease, this association should not be taken to mean that all patients with subjective neurocognitive dysfunction have Lyme disease; such symptoms can also be found not only among patients with other infectious and non-infectious inflammatory conditions, but also among otherwise healthy persons.1 Even among patients with Lyme disease, the presence of subjective neurocognitive symptoms is more likely to reflect systemic inflammation than genuine central nervous system infection. This point was highlighted in a study of patients with erythema migrans, among whom the presence of symptoms such as headache, vertigo, paresthesias, and memory, concentration, or sleep disturbance did not predict the presence of cerebrospinal fluid (CSF) pleocytosis indicative of authentic central nervous system infection.5 If after careful consideration, neuroborreliosis is entertained as a diagnostic possibility, can laboratory testing help confirm or exclude the diagnosis? For patients with syndromes compatible with Lyme neuroborreliosis, such as seventh nerve palsy or aseptic meningitis, the positive predictive value of serologic testing is high, as is the negative predictive value of acute followed by convalescent testing. IgG immunoblots are particularly important, especially when considering the high prevalence of false-positive IgM immunoblots—perhaps the most common pitfall of Lyme diagnostics. In one representative series, more than 50% of patients with headaches and nearly 25% with neurocognitive symptoms thought potentially attributable to Lyme disease were due to something else, as a false-positive IgM immunoblot was the only test result suggesting B burgdorferi infection.6 The high (27.5%) prevalence of false-positive IgM immunoblots in this series is one of the primary reasons screening for Lyme disease is discouraged when the diagnosis is improbable. The IgM immunoblot is only useful for patients with illnesses of less than 4 weeks’ duration that are compatible with early Lyme disease. After 4 weeks of illness, Lyme IgM immunoblots should be disregarded irrespective of their reported result. The attribution of IgG immunoblot seropositivity to a patient’s illness still requires clinical judgment; a positive IgG immunoblot is nondiagnostic without a compatible clinical syndrome. Low probability testing often lands patients in consultants’ offices, creating challenges explaining results and countermanding the often patient-driven inclination to “just try antibiotics” that may lead to harmful drug adverse effects without chance of benefit. This approach may also delay arrival at the correct diagnosis and treatment. In the event that the diagnosis of neuroborreliosis remains plausible but uncertainty remains, assessing the ratio of B burgdorferi antibodies between CSF and blood can be useful. Isolated CSF antibody testing is discouraged, as correcting for blood antibody levels is essential to distinguish intrathecal antibody production from spillage into the CSF. A ratio of 1.3 or more is usually considered positive, but as with all antibody-based Lyme diagnostics, considering the clinical context is essential. Furthermore, elevated CSF antibody levels can persist even after adequate antibiotic therapy. Patients with persistently positive serologic test results and ongoing symptoms can present a challenge, especially when a compelling alternative diagnosis has not been discovered. Unlike syphilis, where the rapid plasma reagin titer declines with adequate treatment, there is no test of cure for Lyme disease. Patients without new symptoms or findings should not be retested or retreated because seropositivity, including IgM, can persist for decades. For patients with a history of Lyme disease and persistent symptoms, the ineffectiveness of additional courses of antibiotic therapy in those previously treated should stay further antibiotics.7 While B burgdorferi infection can cause neurologic disease, familiar presentations far outnumber atypical manifestations. Consultants should base neuroborreliosis diagnoses on epidemiology, objective findings, and sound laboratory testing. When Lyme disease is deemed unlikely, educating patients and referring physicians alike will help avoid unnecessary antibiotic therapy and direct consideration of alternative diagnoses. While Lyme disease is no imposter, syphilis’ title as the Great Imitator remains secure for now.

Constrictive pleuropericarditis: a dominant clinical manifestation in Whipple's disease.

BackgroundWhipple’s disease is a rare, multisystemic, chronic infectious disease which classically presents as a wasting illness characterized by polyarthralgia, diarrhea, fever, and lymphadenopathy. Pleuropericardial involvement is a common pathologic finding in patients with Whipple’s disease, but rarely causes clinical symptoms. We report the first case of severe fibrosing pleuropericarditis necessitating pleural decortication in a patient with Whipple’s disease.Case presentationOur patient, an elderly gentleman, had a chronic inflammatory illness dominated by constrictive pericarditis and later severe fibrosing pleuritis associated with a mildly elevated serum IgG4 level. A pericardial biopsy showed dense fibrosis without IgG4 plasmacytic infiltration. The patient received immunosuppressive therapy for possible IgG4-related disease. His poor response to this therapy prompted a re-examination of the diagnosis, including a request for the pericardial biopsy tissue to be stained for Tropheryma whipplei.ConclusionsDespite a high prevalence of pleuropericardial involvement in Whipple’s disease, constrictive pleuropericarditis is rare, particularly as the dominant disease manifestation. The diagnosis of Whipple’s disease is often delayed in such atypical presentations since the etiologic agent, Tropheryma whipplei, is not routinely sought in histopathology specimens of pleura or pericardium. A diagnosis of Whipple’s disease should be considered in middle-aged or elderly men with polyarthralgia and constrictive pericarditis, even in the absence of gastrointestinal symptoms. Although Tropheryma whipplei PCR has limited sensitivity and specificity, especially in the analysis of peripheral blood samples, it may have diagnostic value in inflammatory disorders of uncertain etiology, including cases of polyserositis. The optimal approach to managing constrictive pericarditis in patients with Whipple’s disease is uncertain, but limited clinical experience suggests that a combination of pericardiectomy and antibiotic therapy is of benefit.

Defining Clinical Excellence in Adult Infectious Disease Practice

Excellence in clinical care should be recognized and rewarded. A recent paradigm defined clinical excellence through seven key domains. This work examines ID clinical excellence in these domains, and in doing so highlights the important skill sets of ID physicians.

Human Immunodeficiency Virus and Allergic Bronchopulmonary Aspergillosis: Case Report and Review of Literature

Allergic bronchopulmonary aspergillosis (ABPA) results from a hypersensitivity response to airways colonization with Aspergillus fumigatus, and it occurs most often in individuals with asthma or cystic fibrosis. Allergic bronchopulmonary aspergillosis is an indolent, but potentially progressive, disease in patients. In patients infected with human immunodeficiency virus (HIV), ABPA is rare, and its description in the literature is limited to case reports. We describe the occurrence of ABPA in a 37-year-old woman with well controlled HIV infection. This represents the first documented case of ABPA in an HIV-infected patient whose only pulmonary comorbidity included the ramifications of prior acute respiratory distress syndrome due to Pneumocystis jirovecii pneumonia. We also review prior case reports of ABPA in HIV-infected patients and consider risk factors for its development.