The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

An estimated 15% or more of the cancer burden worldwide is attributable to known infectious agents. We screened colorectal carcinoma and matched normal tissue specimens using RNA-seq followed by host sequence subtraction and found marked over-representation of Fusobacterium nucleatum sequences in tumors relative to control specimens. F. nucleatum is an invasive anaerobe that has been linked previously to periodontitis and appendicitis, but not to cancer. Fusobacteria are rare constituents of the fecal microbiota, but have been cultured previously from biopsies of inflamed gut mucosa. We obtained a Fusobacterium isolate from a frozen tumor specimen; this showed highest sequence similarity to a known gut mucosa isolate and was confirmed to be invasive. We verified overabundance of Fusobacterium sequences in tumor versus matched normal control tissue by quantitative PCR analysis from a total of 99 subjects (p = 2.5 × 10(-6)), and we observed a positive association with lymph node metastasis.

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Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma

Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum.

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Taxonomy, Physiology, and Natural Products of Actinobacteria

Campylobacter jejuni infection is one of the most widespread infectious diseases of the last century. The incidence and prevalence of campylobacteriosis have increased in both developed and developing countries over the last 10 years. The dramatic increase in North America, Europe, and Australia is alarming, and data from parts of Africa, Asia, and the Middle East indicate that campylobacteriosis is endemic in these areas, especially in children. In addition to C. jejuni, there is increasing recognition of the clinical importance of emerging Campylobacter species, including Campylobacter concisus and Campylobacter ureolyticus. Poultry is a major reservoir and source of transmission of campylobacteriosis to humans. Other risk factors include consumption of animal products and water, contact with animals, and international travel. Strategic implementation of multifaceted biocontrol measures to reduce the transmission of this group of pathogens is paramount for public health. Overall, campylobacteriosis is still one of the most important infectious diseases that is likely to challenge global health in the years to come. This review provides a comprehensive overview of the global epidemiology, transmission, and clinical relevance of Campylobacter infection.

Global Epidemiology of Campylobacter Infection

The diagnosis, investigation and particularly management of bronchiectasis has been largely empirical and the subject of relatively few controlled clinical trials. There are no clear guidelines, although an Australian position statement has been published concerning bronchiectasis in children. The purposes of these guidelines were therefore threefold: (1) to identify relevant studies in non-cystic fibrosis (CF) bronchiectasis; (2) to provide guidelines on management based on published studies where possible or a consensus view; and (3) to identify gaps in our knowledge and identify areas for future study.

https://thorax.bmj.com/content/thoraxjnl/65/Suppl_1/i1.full.pdf

British Thoracic Society guideline for non-CF bronchiectasis.

Mycobacterium leprae causes leprosy. M leprae strains collected worldwide have been genetically clonal, which poorly explains the varying severity and clinical features of the disease. We discovered a new Mycobacterium species from 2 patients who died of diffuse lepromatous leprosy (DLL). The Mycobacterium was purified from heavily infected, freshly frozen autopsy liver tissue followed by DNA extraction in 1 case. Paraffin-embedded skin tissue was used for DNA extraction in another case. Six genes of the organism were amplified by polymerase chain reaction, sequenced on cloning or from amplicons, and analyzed. Significant genetic differences with M leprae were found, including a 2.1% divergence of the 16S ribosomal RNA (rRNA) gene, a highly conserved marker of bacterial evolution, and 6% to 14% mismatches among 5 less conserved genes. Phylogenetic analyses of the genes of 16S rRNA, rpoB, and hsp65 indicated that the 2 most related organisms evolved from a common ancestor that had branched from other mycobacteria. These results and the unique clinicopathologic features of DLL led us to propose Mycobacterium lepromatosis sp nov. This species may account for some of the clinical and geographic variability of leprosy. This finding may have implications for the research and diagnosis of leprosy.

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A new Mycobacterium species causing diffuse lepromatous leprosy.

We analyzed clinical and microbiologic features of 115 cases involving rapidly growing mycobacteria (RGM) isolated at the University of Texas M.D. Anderson Cancer Center, Houston (2000-2005) and identified by 16S ribosomal RNA gene sequencing analysis. At least 15 RGM species were included: Mycobacterium abscessus (43 strains [37.4%]), Mycobacterium fortuitum complex (33 strains [28.7%]), and Mycobacterium mucogenicum (28 strains [24.3%]) most common, accounting for 90.4%. Most M abscessus (32/43) were isolated from respiratory sources, whereas most M mucogenicum (24/28) were from blood cultures. Antimicrobial susceptibility tests showed that M abscessus was the most resistant species; M mucogenicum was most susceptible. From blood and catheter sources, 46 strains (40.0%) were isolated; 44 represented bacteremia or catheter-related infections. These infections typically manifested high fever (mean temperature, 38.9 degrees C), with a high number of RGM colonies cultured. All infections resolved with catheter removal and antibiotic therapy. Six strains (M abscessus and M fortuitum only) were from skin, soft tissue, and wound infections. There were 59 strains from respiratory sources, and 28 of these represented definitive to probable infections. Prior lung injuries and coisolation of other pathogenic organisms were common. Overall, 78 RGM strains (67.8%) caused true to probable infections without direct deaths.

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Rapidly growing mycobacteria: clinical and microbiologic studies of 115 cases.

Clinical and microbiologic studies of 50 cases of viridans streptococcal bacteremia in cancer patients were performed. The bacteria were identified to species level by sequencing analysis of the 16S rRNA gene. At least nine Streptococcus spp. were found, including S. mitis (25 strains, 50.0% of 50); currently unnamed Streptococcus spp. (11 strains); S. parasanguis (five strains); S. anginosus (three strains); S. salivarius (two strains); and one strain each of S. gordonii, S. sanguis, S. sobrinus, and S. vestibularis. There were no S. oralis strains. Among 11 antibiotics of nine classes tested, no resistance to vancomycin, linezolid, or quinupristin-dalfopristin was seen. Resistance to penicillin (MIC, 4 to 12 mug/ml) was noted only among S. mitis strains (28.0%, 7/25) and not non-S. mitis strains (0/25) (P = 0.004). Significantly more S. mitis strains than non-S. mitis strains were resistant to fluoroquinolones and to > or =3 classes of antibiotics. Isolation of quinolone-resistant organisms was associated with the prior usage of quinolones (P = 0.002). Quantitative blood cultures showed that the strains resistant to levofloxacin or gatifloxacin were associated with higher colony counts than were their corresponding nonresistant strains. The young and elderly patients also had higher levels of bacteremia caused predominantly by S. mitis. Septic shock was present in 17 (34.0% of 50) patients, and 13 of those cases were caused by S. mitis (P = 0.007). These results suggest that S. mitis is the most common cause of viridans streptococcal bacteremia in cancer patients and is more resistant to antibiotics than other species.

Viridans Streptococci Isolated by Culture from Blood of Cancer Patients: Clinical and Microbiologic Analysis of 50 Cases

The clinical significance and prevalence of Mycobacterium avium and Mycobacterium intracellulare were analyzed in a cohort of 7,472 patients who, from 1999 to 2003, sought care at the University of Texas M.D. Anderson Cancer Center, Houston, and had cultures performed for mycobacteria. Patients were stratified for age, sex, and underlying diseases, and bacteria were identified by 16S rRNA gene sequencing. M. avium was isolated in 62 (0.83%) of 7,472 patients and M. intracellulare in 65 (0.87%). Clinically, only 10 of the 62 (16.2%) patients with M. avium had probable to definite evidence of infection, whereas the majority (83.8%) had weak evidence of infection. Sex and age did not affect the isolation or infection of M. avium. Hematological tumors predisposed to M. avium colonization but not infection. In contrast, 41 of the 65 (63.1%) patients with M. intracellulare had probable to definite infection, a level much higher than those with M. avium (P < 0.001). M. intracellulare was more prevalent in women (1.33% of 3,311) than in men (0.50% of 4,161) (P < 0.001), and underlying diseases had no effect in women. Men with lung cancer had a higher prevalence (1.37%) than men without (0.34%) (4.0-fold; P < 0.001), but it was similar to that in women. A marked age trend for the isolation of M. intracellulare among women was noted: 0.27% (1-fold) for ages of <50 years, 0.85% (3.1-fold) for ages 50 to 59 years, 1.50% (5.6-fold) for ages 60 to 69 years, and 3.74% (13.9-fold) for ages ≥70 years (trend, P < 0.001). The combined rate for women ≥50 was 1.86% (95% confidence interval [1.30 to 2.42%]) (6.9-fold). Together, these results suggest that, among non-AIDS patients, M. intracellulare is more pathogenic and tends to infect women increasingly beyond menopause (age ≥50 years) regardless of underlying disease. The prevalence rate of 1.86% in postmenopausal women suggests the need to further investigate the public health significance of M. intracellulare.

Clinical Significance and Epidemiologic Analyses of Mycobacterium avium and Mycobacterium intracellulare among Patients without AIDS

Records of 31 patients with cancer who did not have known human immunodeficiency virus infection and who developed culture-proven cryptococcosis during the period of 1989-1999 (incidence of 18 cases per 100,000 admissions) were retrospectively reviewed. Several presentations of cryptococcosis were seen, including pulmonary in 19 patients (13 of which were symptomatic), disseminated in 6, meningeal in 3, and other, less common manifestations in 3. Hematologic malignancy (in 20 patients [65%]) was the most common underlying disease. Lymphopenia was present in 19 patients (61%). Previous steroid use was noted in 16 patients (51%). The diagnosis of cryptococcosis was rarely suspected; lung and brain malignancy were frequent initial impressions. Cryptococcosis was diagnosed postmortem in only 2 cases (6%). In cases of both pulmonary and meningeal cryptococcosis, the yield of invasive diagnostic procedures was good. Antifungal treatment was heterogeneous, but only 18% of patients who received it had treatment failure. Fluconazole monotherapy was successful in 92% of patients. In conclusion, cryptococcosis is rare in patients with cancer and appears to have a relatively good diagnostic yield and therapeutic outcome.

Xiang Y. Han

Papers

A new Mycobacterium species causing diffuse lepromatous leprosy.

Rapidly growing mycobacteria: clinical and microbiologic studies of 115 cases.

Viridans Streptococci Isolated by Culture from Blood of Cancer Patients: Clinical and Microbiologic Analysis of 50 Cases

Clinical Significance and Epidemiologic Analyses of Mycobacterium avium and Mycobacterium intracellulare among Patients without AIDS

Cryptococcosis in Patients with Cancer