Leprosy Caused by Mycobacterium lepromatosis.

OBJECTIVES: Leprosy is caused by Mycobacterium leprae or Mycobacterium lepromatosis. This study reviews literature on M lepromatosis and reports on a Mexican family with this infection. METHODS: The review included all primary studies. Family history and surveys were used to uncover the infection cluster. Genome-based differential polymerase chain reactions were designed to detect etiologic agents. RESULTS: Since the discovery of M lepromatosis in 2008, 154 cases of M lepromatosis infection from 11 countries in the Americas and Asia have been reported, with most cases coming from Mexico. These cases included diffuse lepromatous leprosy (DLL) and other leprosy forms. Genomes of M lepromatosis strains have lately been sequenced, revealing 3,271,694 nucleotides and approximately 15% mismatches with M leprae. The Mexican family with leprosy involved the grandfather, mother, and 2 grandsons. The index was the oldest grandson, who manifested DLL and likely contracted the infection from his maternal grandfather approximately 13 years earlier. Family surveys diagnosed DLL in the index patient's mother and borderline leprosy in his brother; both were likely infected by the index patient. M lepromatosis was identified from archived biopsies from the index patient and his mother, while M leprae was excluded. CONCLUSIONS: M lepromatosis is a significant cause of leprosy in Mexico and requires better surveillance and control.

Construction and Analysis of the Complete Genome Sequence of Leprosy Agent Mycobacterium lepromatosis.

Leprosy is caused by Mycobacterium leprae and Mycobacterium lepromatosis. We report construction and analyses of the complete genome sequence of M. lepromatosis FJ924. The genome contained 3,271,694 nucleotides to encode 1,789 functional genes and 1,564 pseudogenes. It shared 1,420 genes and 885 pseudogenes (71.4%) with M. leprae but differed in 1,281 genes and pseudogenes (28.6%). In phylogeny, the leprosy bacilli started from a most recent common ancestor (MRCA) that diverged ~30 million years ago (Mya) from environmental organism Mycobacterium haemophilum. The MRCA then underwent reductive evolution with pseudogenization, gene loss, and chromosomal rearrangements. Analysis of the shared pseudogenes estimated the pseudogenization event ~14 Mya, shortly before species bifurcation. Afterwards, genomic changes occurred to lesser extent in each species. Like M. leprae, four major types of highly repetitive sequences were detected in M. lepromatosis, contributing to chromosomal rearrangements within and after MRCA. Variations in genes and copy numbers were noted, such as three copies of the gene encoding bifunctional diguanylate cyclase/phosphodiesterase in M. lepromatosis, but single copy in M. leprae; 6 genes encoding the TetR family transcriptional regulators in M. lepromatosis, but 11 such genes in M. leprae; presence of hemW gene in M. lepromatosis, but absence in M. leprae; and others. These variations likely aid unique pathogenesis, such as diffuse lepromatous leprosy associated with M. lepromatosis, while the shared genomic features should explain the common pathogenesis of dermatitis and neuritis in leprosy. Together, these findings and the genomic data of M. lepromatosis may facilitate future research and care for leprosy. IMPORTANCE Leprosy is a dreaded infection that still affects millions of people worldwide. Mycobacterium lepromatosis is a recently recognized cause in addition to the well-known Mycobacterium leprae. M. lepromatosis is likely specific for diffuse lepromatous leprosy, a severe form of the infection and endemic in Mexico. This study constructed and annotated the complete genome sequence of M. lepromatosis FJ924 and performed comparative genomic analyses with related mycobacteria. The results afford new and refined insights into the genome size, gene repertoire, pseudogenes, phylogenomic relationship, genome organization and plasticity, process and timing of reductive evolution, and genetic and proteomic basis for pathogenesis. The availability of the complete M. lepromatosis genome may prove to be useful for future research and care for the infection.

Effects of climate changes and road exposure on the rapidly rising legionellosis incidence rates in the United States.

Legionellosis is an infection acquired through inhalation of aerosols that are contaminated with environmental bacteria Legionella spp. The bacteria require warm temperature for proliferation in bodies of water and moist soil. The legionellosis incidence in the United States has been rising rapidly in the past two decades without a clear explanation. In the meantime, the US has recorded consecutive years of above-norm temperature since 1997 and precipitation surplus since 2008. The present study analyzed the legionellosis incidence in the US during the 20-year period of 1999 to 2018 and correlated with concurrent temperature, precipitation, solar ultraviolet B (UVB) radiation, and vehicle mileage data. The age-adjusted legionellosis incidence rates rose exponentially from 0.40/100,000 in 1999 (with 1108 cases) to 2.69/100,000 in 2018 (with 9933 cases) at a calculated annual increase of 110%. In regression analyses, the rise correlated with an increase in vehicle miles driven and with temperature and precipitation levels that have been above the 1901-2000 mean since 1997 and 2008, respectively, suggesting more road exposure to traffic-generated aerosols and promotive effects of anomalous climate. Remarkably, the regressions with cumulative anomalies of temperature and precipitation were robust (R2 ≥ 0.9145, P ≤ 4.7E-11), implying possible changes to microbial ecology in the terrestrial and aquatic environments. An interactive synergy between annual precipitation and vehicle miles was also found in multiple regressions. Meanwhile, the bactericidal UVB radiation has been decreasing, which also contributed to the rising incidence in an inverse correlation. The 2018 legionellosis incidence peak corresponded to cumulative effects of the climate anomalies, vast vehicle miles (3,240 billion miles, 15904 km per capita), record high precipitation (880.1 mm), near record low UVB radiation (7488 kJ/m2), and continued above-norm temperature (11.96°C). These effects were examined and demonstrated in California, Florida, New Jersey, Ohio, and Wisconsin, states that represent diverse incidence rates and climates. The incidence and above-norm temperature both rose most in cold Wisconsin. These results suggest that warming temperature and precipitation surplus have likely elevated the density of Legionella bacteria in the environment, and together with road exposure explain the rapidly rising incidence of legionellosis in the United States. These trends are expected to continue, warranting further research and efforts to prevent infection.

Solar and Climate Effects Explain the Wide Variation in Legionellosis Incidence Rates in the United States.

Legionellosis, an infection caused by the environmental bacteria Legionella spp., has become a significant public health problem in the United States in recent years; however, among the states, the incidence rates vary widely without a clear explanation. This study examined environmental effects on the 2014-to-2016 average annual legionellosis incidence rates in the U.S. states through correlative analyses with long-term precipitation, temperature, solar UV radiation, and sunshine hours. The continental states west of ∼95°W showed low incidence rates of 0.51 to 1.20 cases per 100,000 population, which corresponded to low precipitation, below 750 mm annually. For the eastern states, where precipitation was higher, solar effects were prominent and mixed, leading to wide incidence variation. Robust regressions suggested a dividing line at 40°N: north of this line, rising temperature, mainly from solar heat, raised legionellosis incidence to a peak of 4.25/100,000 in Ohio; south of the line, intensifying sunlight in terms of high UV indices and long sunshine hours prevailed to limit incidence gradually to 0.99/100,000 in Louisiana. On or near the 40°N line were 15 eastern states that had leading legionellosis incidence rates of >2.0/100,000. These states all showed modest environmental parameters. In contrast, the frigid climate in Alaska and the strong year-round solar UV in Hawaii explained the lowest U.S. incidences, 0.14/100,000 and 0.47/100,000, respectively, in these states. The findings of solar and climate effects explain the wide variation of legionellosis incidence rates in the United States and may offer insights into the potential exposure to and prevention of infection.IMPORTANCE Legionellosis, caused by the environmental bacteria Legionella spp., has become a significant public health problem in the United States in recent years, with ∼6,000 cases annually. The present study showed, through a series of correlative analyses with long-term precipitation, temperature, solar UV radiation, and sunshine hours, that these environmental conditions strongly influence the legionellosis incidence rates across the United States in mixed and dynamic fashions. The incidence rates varied remarkably by region, with the highest in Ohio and New York and the lowest in Alaska. A precipitation threshold above 750 mm was required for elevated legionellosis activity. Regression models and dividing lines between regions were established to show the promotive effect of temperature, as well as the inhibitive effects of solar UV and sunshine hours. These findings explain the wide variation of legionellosis incidence rates in the United States. They may also offer insights into potential exposure to and prevention of infection.

Diffuse Lepromatous Leprosy Due to Mycobacterium lepromatosis in Quintana Roo, Mexico.

A 43-year-old woman of Mayan origin from Quintana Roo, Mexico, was diagnosed with diffuse lepromatous leprosy. The etiologic bacillus was determined to be Mycobacterium lepromatosis instead of Mycobacterium leprae. This case likely represents the first report of this leprosy form and its agent in the southeastern tip of Mexico.

Draft Genome Sequence of New Leprosy Agent Mycobacterium lepromatosis.

Mycobacterium lepromatosis is a newly discovered cause of leprosy. Here, we present a near-complete genome of M. lepromatosis from strain FJ924 obtained from a patient who died of leprosy. The genome contained 3,215,823 nucleotides and matched ~87% with the Mycobacterium leprae genome. This genome is likely the smallest of all mycobacterial genomes known to date.

Microbiological and Clinical Studies of Legionellosis in 33 Patients with Cancer.

Legionella, a large group of environmental Gram-negative bacteria, represents an occasional cause of pneumonia. We analyzed the microbiological and clinical features of 33 consecutive cases of Legionella infections that occurred at the University of Texas MD Anderson Cancer Center, Houston, TX, from 2002 to 2014. The Legionella strains were isolated from bronchoscopy specimens (32 strains) and a blood culture (1 strain) and were identified by sequencing analysis of the full-length 16S rRNA gene. The 33 strains involved 12 Legionella species or subspecies: 15 strains of L. pneumophila subsp. pneumophila, 3 strains of L. pneumophila subsp. fraseri or L. pneumophila subsp. pascullei, 4 strains of "L. donaldsonii," 3 strains of L. micdadei, and one each of L. bozemanae, L. feeleii, L. gormanii, L. longbeachae, L. maceachernii, L. parisiensis, L. sainthelensi, and Legionella sp. strain D5382. All patients except one asymptomatic carrier showed pneumonia, including one with concurrent bacteremia. Nine patients died, with this infection being the immediate cause of death in six. Twenty-seven patients had underlying hematologic malignancies. Twenty-three patients were leukopenic. Six patients were recipients of allogeneic hematopoietic stem cell transplant, with their infections caused by five Legionella species. Together, these results suggest that diverse Legionella species infect patients with cancer in the Houston area and its vicinity. The five cases of pneumonia due to L. donaldsonii and Legionella sp. D5382 are likely the first reports of human infection with these organisms.

Microbiological and clinical features of four cases of catheter-related infection by Methylobacterium radiotolerans.

Four cases of central venous catheter-related Methylobacterium radiotolerans infection are presented here. The patients were all long-term catheter carriers with an underlying diagnosis of leukemia, and they mostly manifested fevers. The isolated bacterial strains all showed far better growth on buffered charcoal yeast extract agar during the initial isolation and/or subcultures than they did on sheep blood or chocolate agar. This microbiological feature may improve the culture recovery of this fastidious pink Gram-negative bacillus that has rarely been isolated in clinical microbiology laboratories.

Nocardiosis in 132 patients with cancer: microbiological and clinical analyses.

OBJECTIVES: To correlate the microbiological and clinical features of infections caused by Nocardia species. METHODS: We determined the species and drug susceptibility of 138 Nocardia strains isolated from 132 patients at the University of Texas M. D. Anderson Cancer Center (Houston, TX) from 2002 through 2012 and analyzed the clinical features. RESULTS: The 132 patients included 82 men and 50 women with a mean age of 59.1 years. All except two had underlying cancer, and 47 (35.6%) also received a stem cell transplant. These patients experienced 136 episodes of Nocardia infection, including pulmonary infection, abscess of deep skin and soft tissue, bacteremia and dissemination, and brain abscess. The 138 Nocardia strains involved 27 species, of which 20 species have been described since 2000. Common species included Nocardia nova, Nocardia cyriacigeorgica, Nocardia farcinica, and Nocardia abscessus, together accounting for 59.4%. N nova caused most bacteremia cases, whereas N farcinica caused most of the skin and brain infections. Infections with a few recent species likely represented first confirmation or report of human infections. Antimicrobial susceptibility tests of 117 strains showed that they were all susceptible to trimethoprim-sulfamethoxazole and linezolid but variably susceptible to other drugs depending on species. Most patients who were treated for the infection showed improvement or resolution. CONCLUSIONS: Diverse Nocardia species can cause secondary infections in patients with cancer. Timely species identification and antimicrobial susceptibility tests may guide treatment.

Analysis of the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis in four countries.

OBJECTIVES: To differentiate the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis and correlate them with geographic distribution and clinicopathologic features. METHODS: Species-specific polymerase chain reactions were used to detect each bacillus in archived skin biopsy specimens from patients with leprosy from Brazil (n = 52), Malaysia (n = 31), Myanmar (n = 9), and Uganda (n = 4). Findings were correlated with clinical and pathologic data. RESULTS: Etiologic species was detected in 46 of the 52 Brazilian patients, including 36 patients with M leprae, seven with M lepromatosis, and three with both bacilli. The seven patients with sole M lepromatosis all had tuberculoid leprosy, whereas only nine of the 36 patients infected with M leprae exhibited this type, and the rest were lepromatous (P < .001). All patients with dual infections had lepromatous leprosy. Of the nine patients from Myanmar, six were test positive: four with M leprae and two with M lepromatosis. Of the Malaysian and Ugandan patients, only M leprae was detected in 27 of the 31 Malaysians and two of the four Ugandans. CONCLUSIONS: The leprosy agents vary in geographic distribution. Finding M lepromatosis in Brazil and Myanmar suggests wide existence of this newly discovered species. The leprosy manifestations likely vary with the etiologic agents.

GyrB polymorphisms accurately assign invasive viridans group streptococcal species.

Viridans group streptococci (VGS) are a heterogeneous group of medically important bacteria that cannot be accurately assigned to a particular species using conventional phenotypic methods. Although multilocus sequence analysis (MLSA) is considered the gold standard for VGS species-level identification, MLSA is not yet feasible in the clinical setting. Conversely, molecular methods, such as sodA and 16S rRNA gene sequencing, are clinically practical but not sufficiently accurate for VGS species-level identification. Here, we present data regarding the use of an ∼ 400-nucleotide internal fragment of the gene encoding DNA gyrase subunit B (GyrB) for VGS species-level identification. MLSA, internal gyrB, sodA, full-length, and 5' 16S gene sequences were used to characterize 102 unique VGS blood isolates collected from 2011 to 2012. When using the MLSA species assignment as a reference, full-length and 5' partial 16S gene and sodA sequence analyses failed to correctly assign all strains to a species. Precise species determination was particularly problematic for Streptococcus mitis and Streptococcus oralis isolates. However, the internal gyrB fragment allowed for accurate species designations for all 102 strains. We validated these findings using 54 VGS strains for which MLSA, 16S gene, sodA, and gyrB data are available at the NCBI, showing that gyrB is superior to 16S gene and sodA sequence analyses for VGS species identification. We also observed that specific polymorphisms in the 133-amino acid sequence of the internal GyrB fragment can be used to identify invasive VGS species. Thus, the GyrB amino acid sequence may offer a more practical and accurate method for classifying invasive VGS strains to the species level.

Septic transfusion reactions during blood transfusion via indwelling central venous catheters.

BACKGROUND: Transfusion of blood products requires a vascular port. Use of an indwelling central venous catheter (CVC) provides this port readily and safely in general; however, potential risks require assessment. STUDY DESIGN AND METHODS: The objective was to examine septic reactions to blood transfusions performed via CVCs owing to subclinical microbial catheter colonization. All transfusion reactions that occurred from 2007 to 2011 at The University of Texas MD Anderson Cancer Center were analyzed and correlated with microbiology culture results. Data on the reactions, including vascular access via a catheter or peripheral venipuncture, were collected prospectively. RESULTS: A total of 999 reactions were reported, with an incidence of two per 1000 transfusion events. A total of 738 reactions occurred in 642 patients during transfusion through a CVC. Among them, 606 reactions occurred in patients that had cultures of blood samples drawn within 7 days before or after reaction. Sixty of these (9.9%) had at least one significant microorganism isolated from their catheters and/or peripheral blood. The blood culture results and timing suggested that these patients likely had catheter-related bloodstream infections caused by transfusion through a CVC with subclinical microbial colonization. Fever and chills occurred in 35 of these patients (58%), which resembled febrile nonhemolytic transfusion reactions. Culture results of the transfused blood products, although not performed in all cases, were mostly negative in these CVC-related reactions. CONCLUSION: Blood transfusion through an indwelling CVC may lead to septic reaction owing to subclinical microbial colonization. This risk should be considered before transfusion and during investigation of transfusion reactions.

On the age of leprosy.

Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae and the newly discovered Mycobacterium lepromatosis. Human leprosy has been documented for millennia in ancient cultures. Recent genomic studies of worldwide M. leprae strains have further traced it along global human dispersals during the past ∼ 100,000 years. Because leprosy bacilli are strictly intracellular, we wonder how long humans have been affected by this disease-causing parasite. Based on recently published data on M. leprae genomes, M. lepromatosis discovery, leprosy bacilli evolution, and human evolution, it is most likely that the leprosy bacilli started parasitic evolution in humans or early hominids millions of years ago. This makes leprosy the oldest human-specific infection. The unique adaptive evolution has likely molded the indolent growth and evasion from human immune defense that may explain leprosy pathogenesis. Accordingly, leprosy can be viewed as a natural consequence of a long parasitism. The burden of leprosy may have affected minor selection on human genetic polymorphisms.

Subspecies identification and significance of 257 clinical strains of Mycobacterium avium.

Mycobacterium avium is abundant in the environment. It has four subspecies of three types: the human or porcine type, M. avium subsp. hominissuis; the bird type, including M. avium subsp. avium serotype 1 and serotype 2, 3 (also M. avium subsp. silvaticum); and the ruminant type, M. avium subsp. paratuberculosis. We determined the subspecies of 257 M. avium strains isolated from patients at the M.D. Anderson Cancer Center from 2001 to 2010 and assessed their clinical significance. An assay of multiplex PCR was used for the typing. Results showed M. avium subsp. hominissuis to be most common (n = 238, 92.6%), followed by M. avium subsp. avium serotype 1 (n = 12, 4.7%) and serotype 2, 3 (n = 7, 2.7%). No strains of M. avium subsp. paratuberculosis were found. Of the 238 patients with M. avium subsp. hominissuis, 65 (27.3%) showed evidence of definite or probable infections, mostly in the respiratory tract, whereas the rest had weak evidence of infection. The bird-type subspecies, despite being infrequently isolated, caused relatively more definite and probable infections (10 of 19 strains, 52.6%). Overall, women of 50 years of age or older were more prone to M. avium infection than younger women or men of all ages were. We therefore conclude that M. avium subsp. hominissuis is the dominant M. avium subspecies clinically, that the two bird-type subspecies do cause human infections, and that M. avium infects mainly postmenopausal women. The lack of human clinical isolation of the ruminant type subspecies may need further investigation.

Rapidly growing mycobacterial bloodstream infections.

About 20 species of rapidly growing mycobacteria species that are capable of infecting human beings and causing bloodstream infections have been identified. Many more of these species are being discovered worldwide, especially in resource-poor settings. These microorganisms have been known to cause outbreaks and pseudo-outbreaks. Although rapidly growing mycobacteria are not highly virulent or life threatening, they have a high predisposition to create biofilms and to colonise and infect intravascular catheters. Early detection and identification of specific species can help to estimate predictable antimicrobial susceptibility patterns. However, because susceptibility data originate from developed countries, studies in resource-poor settings urgently need to be done. The best outcome of cure without recurrence depends on a combination of at least 4 weeks of treatment with two or more active antimicrobial agents, plus removal of the intravascular catheter. We review and discuss the epidemiology, pathogenesis, diagnosis, management, and outcomes of rapidly growing mycobacterial bloodstream infections.

Severe leprosy reactions due to Mycobacterium lepromatosis.

Leprosy is caused by the well-known Mycobacterium leprae and the newly discovered M lepromatosis. Here, the authors describe 2 cases of leprosy with unusual clinical presentation caused by M lepromatosis. The patients, a 32-year-old man and a 50-year-old woman, both of Mexican origin, manifested high fever, lymphadenopathy and florid skin lesions in the form of erythema nodosum and Lucio's phenomenon as the first clinical presentation. Heavy infiltration of acid-fast bacilli was identified in the tissues that led to the diagnosis of lepromatous leprosy or diffuse leprosy. The patients were treated with multidrug regimen and responded appropriately. From the lymph node tissue, the authors showed the bacillus to be M lepromatosis, not M leprae as presumed previously, by differential polymerase chain reactions and analysis of gene sequences. These cases add to the growing studies on this organism, expand its endemic regions in Mexico and provide more clinical insight.

Cytokine gene polymorphisms affect reactivation of cytomegalovirus in patients with cancer.

Reactivation of cytomegalovirus (CMV) in the bloodstream may occur upon severe immune defect or suppression during lifetime. We performed a case controlled study to probe the effects of the host cytokine gene single nucleotide polymorphisms (SNPs) on CMV reactivation. The study subjects were patients with cancer but without stem cell transplantation. The cases were patients tested positive for CMV pp65 antigenemia and the controls were those tested negative. Each case was matched to two controls for similar underlying disease, sex, age, and CMV antibody test status. Ninety cases and 182 controls were chosen and typed for 48 SNPs within 13 cytokines. Alleles of three cytokines were found to be significantly associated with CMV reactivation. Associated with risk of CMV reactivation were the TGFß1-2 allele (10C and 25G) with a hazard ratio (HR) of 1.97% and 95% confidence interval (CI) of 1.14-3.41 and the IL-4-3 allele (-1098T, -590T, and -33T) (HR, 2.08) (95% CI, 1.19-3.63); associated with protection was the IL-2-2 allele (-330T and +166G) (HR, 0.58) (95% CI, 0.35-0.97). Gene dosage, synergism, and antagonism among these alleles were also observed. Our results suggest roles of immunogenetic variations on the immunity against CMV, which may allow clinical CMV risk stratification. Further studies of these alleles are warranted.