Life Is Not Fair.

A pediatrian's elegy to a dear friend recounts in this narrative medicine essay how the obstacles from cancer did not impede her from living fully, allowing the friends to share life's pleasures for many years.

Hib Vaccines: Their Impact on Haemophilus influenzae Type b Disease.

Haemophilus influenzae serotype b (Hib) is an important cause of serious, invasive infections, particularly in young children. Since 1985, a series of vaccines composed of the type b capsular polysaccharide polyribosylribitol phosphate (PRP), followed by PRP conjugated to various proteins, have been licensed for use in the United States and worldwide. The conjugated vaccines offer increased immunogenicity and prolonged durability of immune protection compared to the plain PRP vaccine and increasingly are combined with other childhood vaccines for decreased cost and increased ease of vaccination. Hib vaccines have a very favorable safety profile, have been found to be either cost-saving or cost-effective by many public health agencies, and, in most countries, are initiated during early infancy as part of routine childhood immunization programs. As a result of widespread use of the vaccines, the incidence of Hib infections, and their associated morbidity and mortality, has fallen dramatically across the globe. Yet, many children remain unimmunized or underimmunized against Hib, particularly in limited-resource countries. Future efforts to further reduce the disease burden of Hib infections remain a high priority.

Remembering and Enhancing the Impact of Women in Infectious Diseases.

Following the establishment of the Infectious Diseases Society of America (IDSA), women played a minor role as IDSA leaders, awards recipients, and presenters at the national meeting. Since the formation of the IDSA Women's Committee in 1992, women have played an increasing role in all of these domains of the Society. Two subsequent IDSA task forces have emphasized the importance of women, and other unrepresented minorities, to the success of the core missions of the Society. Ongoing efforts to maintain the presence of women and their unique talents, experiences, and understandings in the Society will sustain the strengths of IDSA.

Acute Flaccid Myelitis: Lessons From Polio.

With the eradication of poliomyelitis in the United States, the appearance of acute flaccid myelitis outbreaks has raised questions regarding their causation. Review of the epidemiology, clinical aspects, and laboratory findings of bygone cases of poliomyelitis have revealed shows important similarities with those of newer cases of acute flaccid myelitis. Many occurrences are preceded by an apparent viral illness, and a number of viruses, particularly enteroviruses A71 and D68, can be isolated from respiratory or stool specimens. Our inability to detect these viruses in cerebrospinal fluid samples from these patients does not eliminate them as etiologic agents, because poliovirus is often not detected in cerebrospinal fluid samples of patients with paralysis caused by poliomyelitis.

Pediatric Infectious Diseases Meets the Future.

Pediatric infectious diseases physicians are dedicated to the diagnosis, prevention, and management of infections in children. As such, we play large, and important, roles in the clinical care of children from birth to late adolescence and in infection prevention, antimicrobial stewardship, research pertaining to infections, public health, international and global health, and advocacy for children's health. Furthermore, we are critical to the education of future physicians (in general), pediatricians, and infectious diseases doctors. In addition to diagnosing and treating bacterial, fungal, viral, and parasitic infections known through the ages, we have been at the forefront of meeting today's new infectious threats to children's health, which include the following: antibiotic-resistant organisms; hospital-acquired infections; global outbreaks such as Ebola, Zika, human immunodeficiency virus-acquired immune deficiency syndrome, and new strains of influenza; infections in immunocompromised children; vaccine-preventable infections; the inefficient use of medical resources; and the high cost of medical care.

Multifaceted but Invisible: Perceptions of the Value of a Pediatric Cognitive Specialty.

BACKGROUND: Systems for standardizing physician payment have been shown to undervalue cognitive clinical encounters. Because health care reform emphasizes value-based approaches, we need an understanding of the way pediatric cognitive specialties are used to contribute to the provision of high-value care. We sought to investigate how clinical and administrative stakeholders perceive the value of pediatric infectious disease (PID) specialists. METHODS: We conducted qualitative interviews with a purposive sample of physicians and administrators from 5 hospitals across the United States in which children are cared for. All interviews were transcribed and systematically analyzed for common themes. RESULTS: We interviewed 97 stakeholders. Analysis revealed the following 3 domains of value: clinical, organizational, and communicative. Clinically, PID specialists were perceived to be highly valuable in treating patients with unusual infections that respond poorly to therapy, in optimizing the use of antimicrobial agents and in serving as outpatient homes for complex patients. Respondents perceived that PID specialists facilitate communication with patients and their families, the health care team and the media. PID specialists were perceived to generate value by participating in systemwide activities, including antimicrobial stewardship and infection prevention. Despite this, much of the valuable work PID specialists perform is difficult to measure causing some administrative stakeholders to question how many PID specialists are necessary to achieve high-quality care. CONCLUSIONS: With our findings, we suggest that pediatric cognitive specialties contribute value in multiple ways to the health care delivery system. Many of these domains are difficult to capture by using current metrics, which may lead administrators to overlook valuable work and to under-allocate resources.

Into Darkness and Silence: What Caused Helen Keller's Deafblindness?

In 1882, at 19 months of age, Helen Keller developed a febrile illness that left her both deaf and blind. Historical biographies attribute the illness to rubella, scarlet fever, encephalitis, or meningitis. This analysis of her illness suggests she likely had bacterial meningitis, caused by Neisseria meningitidis or possibly Haemophilus influenzae.

Capsule Typing of Haemophilus influenzae by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry.

Encapsulated Haemophilus influenzae strains belong to type-specific genetic lineages. Reliable capsule typing requires PCR, but a more efficient method would be useful. We evaluated capsule typing by using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Isolates of all capsule types (a-f and nontypeable; n = 258) and isogenic capsule transformants (types a-d) were investigated. Principal component and biomarker analyses of mass spectra showed clustering, and mass peaks correlated with capsule type-specific genetic lineages. We used 31 selected isolates to construct a capsule typing database. Validation with the remaining isolates (n = 227) showed 100% sensitivity and 92.2% specificity for encapsulated strains (a-f; n = 61). Blinded validation of a supplemented database (n = 50) using clinical isolates (n = 126) showed 100% sensitivity and 100% specificity for encapsulated strains (b, e, and f; n = 28). MALDI-TOF mass spectrometry is an accurate method for capsule typing of H. influenzae.

Haemophilus influenzae Type b Invasive Disease in Amish Children, Missouri, USA, 2014.

During 5 months in 2014, three Amish children in Missouri, USA, were diagnosed with invasive Haemophilus influenzae type b infection. Two were rural neighbors infected with a genetically similar rare strain, sequence type 45. One child had recently traveled, raising the possibility of maintenance of this strain among unvaccinated carriers in Amish communities.

Comparative Genomic Analysis of Haemophilus haemolyticus and Nontypeable Haemophilus influenzae and a New Testing Scheme for Their Discrimination.

Haemophilus haemolyticus has been recently discovered to have the potential to cause invasive disease. It is closely related to nontypeable Haemophilus influenzae (NT H. influenzae). NT H. influenzae and H. haemolyticus are often misidentified because none of the existing tests targeting the known phenotypes of H. haemolyticus are able to specifically identify H. haemolyticus Through comparative genomic analysis of H. haemolyticus and NT H. influenzae, we identified genes unique to H. haemolyticus that can be used as targets for the identification of H. haemolyticus A real-time PCR targeting purT (encoding phosphoribosylglycinamide formyltransferase 2 in the purine synthesis pathway) was developed and evaluated. The lower limit of detection was 40 genomes/PCR; the sensitivity and specificity in detecting H. haemolyticus were 98.9% and 97%, respectively. To improve the discrimination of H. haemolyticus and NT H. influenzae, a testing scheme combining two targets (H. haemolyticus purT and H. influenzae hpd, encoding protein D lipoprotein) was also evaluated and showed 96.7% sensitivity and 98.2% specificity for the identification of H. haemolyticus and 92.8% sensitivity and 100% specificity for the identification of H. influenzae, respectively. The dual-target testing scheme can be used for the diagnosis and surveillance of infection and disease caused by H. haemolyticus and NT H. influenzae.

Coaggregation occurs between microorganisms isolated from different environments.

Coaggregation, the specific recognition and adherence of different microbial species, is thought to enhance biofilm formation. To date, no studies have focused on the ability of microorganisms isolated from a broad range of environments to coaggregate with each other and it is unclear whether coaggregation promotes the transmission of microorganisms between environmental niches. We aimed to evaluate the coaggregation ability of 29 bacteria and one fungus, isolated from a range of different environments, and to characterize the cell-surface polymers that mediate coaggregation between selected pairs. Strains were categorized as belonging to one of the four microbial archetypes: aquatic, broad environment, human opportunistic pathogen or human oral. A total of 23 of the 30 strains (77%) coaggregated with at least one other and 21/30 (70%) coaggregated with strains belonging to other archetypes. Nasopharyngeal bacteria belonging to the human opportunistic pathogen archetype showed the least number of coaggregations, and five Haemophilus influenzae strains did not coaggregate. Protease and sugar treatments indicated that coaggregation between strains of different archetypes was often mediated by lectin-saccharide interactions (9 of 15 evaluated pairs). In conclusion, coaggregation can occur between taxonomically disparate species isolated from discrete environments. We propose that these organisms be labeled as 'cross-environment coaggregating organisms'. The ability to coaggregate may aid species to colonize non-indigenous biofilms.

Comparative Profile of Heme Acquisition Genes in Disease-Causing and Colonizing Nontypeable Haemophilus influenzae and Haemophilus haemolyticus.

Nontypeable Haemophilus influenzae (NTHI) are Gram-negative bacteria that colonize the human pharynx and can cause respiratory tract infections, such as acute otitis media (AOM). Since NTHI require iron from their hosts for aerobic growth, the heme acquisition genes may play a significant role in avoiding host nutritional immunity and determining virulence. Therefore, we employed a hybridization-based technique to compare the prevalence of five heme acquisition genes (hxuA, hxuB, hxuC, hemR, and hup) between 514 middle ear strains from children with AOM and 235 throat strains from healthy children. We also investigated their prevalences in 148 Haemophilus haemolyticus strains, a closely related species that colonizes the human pharynx and is considered to be nonpathogenic. Four out of five genes (hxuA, hxuB, hxuC, and hemR) were significantly more prevalent in the middle ear strains (96%, 100%, 100%, and 97%, respectively) than in throat strains (80%, 92%, 93%, and 85%, respectively) of NTHI, suggesting that strains possessing these genes have a virulence advantage over those lacking them. All five genes were dramatically more prevalent in NTHI strains than in H. haemolyticus, with 91% versus 9% hxuA, 98% versus 11% hxuB, 98% versus 11% hxuC, 93% versus 20% hemR, and 97% versus 34% hup, supporting their potential role in virulence and highlighting their possibility to serve as biomarkers to distinguish H. influenzae from H. haemolyticus. In summary, this study demonstrates that heme acquisition genes are more prevalent in disease-causing NTHI strains isolated from the middle ear than in colonizing NTHI strains and H. haemolyticus isolated from the pharynx.

What the pediatrician should know about non-typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) live exclusively in the pharynges of humans and are increasingly recognized as pathogens that cause both localized infections of the respiratory tract (middle ear spaces, sinuses, and bronchi) and systemic infections such as bacteraemia and pneumonia. Only one vaccine antigen of NTHi, Protein D, has been extensively studied in humans and its efficacy in preventing NTHi otitis media is modest. Recent genetic analyses reveal that NTHi are closely related to Haemophilus haemolyticus (Hh), previously thought to be a non-pathogenic commensal of the pharynx. This review discusses the differences between the pathogenic potential of encapsulated and non-typeable Hi. In addition, information on the lifestyles and bacterial characteristics of NTHi and Hh as they pertain to their pathogenic capacities and the value of the Haemophilus taxonomy to clinicians are presented. Further, the epidemiology and mechanisms of NTHi antibiotic resistance, which include production of ß-lactamase and alterations of penicillin-binding protein 3, are reviewed, as are the challenges of vaccine antigen discovery in NTHi.

Prevalence, distribution, and sequence diversity of hmwA among commensal and otitis media non-typeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae (NTHi) are Gram-negative coccobacilli that colonize the human pharynx, their only known natural reservoir. Adherence to the host epithelium facilitates NTHi colonization and marks one of the first steps in NTHi pathogenesis. Epithelial cell attachment is mediated, in part, by a pair of high molecular weight (HMW) adhesins that are highly immunogenic, antigenically diverse, and display a wide range of amino acid diversity both within and between isolates. In this study, the prevalence of hmwA, which encodes the HMW adhesin, was determined for a collection of 170 NTHi isolates recovered from the middle ears of children with otitis media (OM isolates) or throats or nasopharynges of healthy children (commensal isolates) from Finland, Israel, and the U.S. Overall, hmwA was detected in 61% of NTHi isolates and was significantly more prevalent (P=0.004) among OM isolates than among commensal isolates; the prevalence ratio comparing hmwA prevalence among ear isolates with that of commensal isolates was 1.47 (95% CI (1.12, 1.92)). Ninety-five percent (98/103) of the hmwA-positive NTHi isolates possessed two hmw loci. To advance our understanding of hmwA binding sequence diversity, we determined the DNA sequence of the hmwA binding region of 33 isolates from this collection. The average amino acid identity across all hmwA sequences was 62%. Phylogenetic analyses of the hmwA binding revealed four distinct sequence clusters, and the majority of hmwA sequences (83%) belonged to one of two dominant sequence clusters. hmwA sequences did not cluster by chromosomal location, geographic region, or disease status.

Otitis media associated polymorphisms in the hemin receptor HemR of nontypeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae (NTHi) colonize the human pharynx asymptomatically, and are also an important cause of otitis media (OM). Previous studies have demonstrated that some genes are more prevalent in OM-causing NTHi strains than in commensal strains, suggesting a role in virulence. These studies, however, are unable to investigate the possible associations between gene polymorphisms and disease. This study examined amino acid polymorphisms and sequence diversity in a potential virulence gene, the hemin receptor hemR, from a previously characterized NTHi strain collection containing both commensal and OM organisms to identify possible associations between the polymorphisms and otitis media. The full open reading frame of hemR was sequenced from a total of 146 NTHi isolates, yielding a total of 47 unique HemR amino acid sequences. The predicted structure of HemR showed substantial similarity to a class of monomeric TonB dependent, ligand-gated channels involved in iron acquisition in other gram negative bacteria. Fifteen amino acid polymorphisms were significantly more prevalent at the 90% confidence level among commensal compared to OM isolates. Upon controlling for the confounding effect of population structure, over half of the polymorphism-otitis media relationships lost statistical significance, emphasizing the importance of assessing the effect of population structure in association studies. The seven polymorphisms that retained significance were dispersed throughout the protein in various functional and structural domains, including the signal peptide, N-terminal plug domain, and intra- and extracellular loops. The alternate amino acid of only one of these seven polymorphisms was more common among OM isolates, demonstrating a strong trend toward the consensus sequence among disease causing NTHi. We hypothesize that variability at these positions in HemR may result in a reduced ability to acquire iron, rendering NTHi with such versions of the gene less fit for survival in the middle ear environment.

Phase variation and host immunity against high molecular weight (HMW) adhesins shape population dynamics of nontypeable Haemophilus influenzae within human hosts.

Nontypeable Haemophilus influenzae (NTHi) is a bacterium that resides within the human pharynx. Because NTHi is human-restricted, its long-term survival is dependent upon its ability to successfully colonize new hosts. Adherence to host epithelium, mediated by bacterial adhesins, is one of the first steps in NTHi colonization. NTHi express several adhesins, including the high molecular weight (HMW) adhesins that mediate attachment to the respiratory epithelium where they interact with the host immune system to elicit a strong humoral response. hmwA, which encodes the HMW adhesin, undergoes phase variation mediated by 7-base pair tandem repeats located within its promoter region. Repeat number affects both hmwA transcription and HMW-adhesin production such that as the number of repeats increases, adhesin production decreases. Cells expressing large amounts of HMW adhesins may be critical for the establishment and maintenance of NTHi colonization, but they might also incur greater fitness costs when faced with an adhesin-specific antibody-mediated immune response. We hypothesized that the occurrence of large deletion events within the hmwA repeat region allows NTHi cells to maintain adherence in the presence of antibody-mediated immunity. To study this, we developed a mathematical model, incorporating hmwA phase variation and antibody-mediated immunity, to explore the trade-off between bacterial adherence and immune evasion. The model predicts that antibody levels and avidity, catastrophic loss rates, and population carrying capacity all significantly affected numbers of adherent NTHi cells within a host. These results suggest that the occurrence of large, yet rare, deletion events allows for stable maintenance of a small population of adherent cells in spite of HMW adhesin specific antibody-mediated immunity. These adherent subpopulations may be important for sustaining colonization and/or maintaining transmission.