Mini Tracheostomy for Obstructive Sleep Apnea: An Evidence Based Proposal.

Objective. To search for articles evaluating the use of tracheostomies (either permanent stomas or tracheostomy tubes) in adult obstructive sleep apnea (OSA) patients and to evaluate the potential for the use of mini tracheostomies as treatment for OSA. Study Design. Systematic review. Methods. Nine databases were searched from inception through July 21, 2015. Results. The overall tracheostomy search yielded 516 articles, of which eighteen studies provided polysomnographic data. No study was identified (empty review) for the use of mini tracheostomies for treating OSA. The mini tracheostomy search yielded ninety-five articles which describe findings for either mini tracheostomy kits (inner cannula diameter of 4 mm) or the performance of mini tracheotomies. Six articles described the use of mini tracheostomies as a temporary procedure to relieve acute upper airway obstruction and none described the use for OSA. For tracheostomy stomal sites, suturing the skin directly to the tracheal rings with defatting can minimize stomal site collapse. The smallest tracheostomy stomal size that can successfully treat OSA has not been described. Conclusion. Mini tracheostomies as small as 4 mm have been successfully used in the short term to relieve upper airway obstruction. Given that polysomnography data are lacking, additional research is needed.

Haemophilus responses to nutritional immunity: epigenetic and morphological contribution to biofilm architecture, invasion, persistence and disease severity.

In an effort to suppress microbial outgrowth, the host sequesters essential nutrients in a process termed nutritional immunity. However, inflammatory responses to bacterial insult can restore nutritional resources. Given that nutrient availability modulates virulence factor production and biofilm formation by other bacterial species, we hypothesized that fluctuations in heme-iron availability, particularly at privileged sites, would similarly influence Haemophilus biofilm formation and pathogenesis. Thus, we cultured Haemophilus through sequential heme-iron deplete and heme-iron replete media to determine the effect of transient depletion of internal stores of heme-iron on multiple pathogenic phenotypes. We observed that prior heme-iron restriction potentiates biofilm changes for at least 72 hours that include increased peak height and architectural complexity as compared to biofilms initiated from heme-iron replete bacteria, suggesting a mechanism for epigenetic responses that participate in the changes observed. Additionally, in a co-infection model for human otitis media, heme-iron restricted Haemophilus, although accounting for only 10% of the inoculum (90% heme-iron replete), represented up to 99% of the organisms recovered at 4 days. These data indicate that fluctuations in heme-iron availability promote a survival advantage during disease. Filamentation mediated by a SulA-related ortholog was required for optimal biofilm peak height and persistence during experimental otitis media. Moreover, severity of disease in response to heme-iron restricted Haemophilus was reduced as evidenced by lack of mucosal destruction, decreased erythema, hemorrhagic foci and vasodilatation. Transient restriction of heme-iron also promoted productive invasion events leading to the development of intracellular bacterial communities. Taken together, these data suggest that nutritional immunity, may, in fact, foster long-term phenotypic changes that better equip bacteria for survival at infectious sites.

Ferric uptake regulator and its role in the pathogenesis of nontypeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae (NTHi) is a commensal microorganism of the human nasopharynx, and yet is also an opportunistic pathogen of the upper and lower respiratory tracts. Host microenvironments influence gene expression patterns, likely critical for NTHi persistence. The host sequesters iron as a mechanism to control microbial growth, and yet iron limitation influences gene expression and subsequent production of proteins involved in iron homeostasis. Careful regulation of iron uptake, via the ferric uptake regulator Fur, is essential in multiple bacteria, including NTHi. We hypothesized therefore that Fur contributes to iron homeostasis in NTHi, is critical for bacterial persistence, and likely regulates expression of virulence factors. Toward this end, fur was deleted in the prototypic NTHi clinical isolate, 86-028NP, and we assessed gene expression regulated by Fur. As expected, expression of the majority of genes that encode proteins with predicted roles in iron utilization was repressed by Fur. However, 14 Fur-regulated genes encode proteins with no known function, and yet may contribute to iron utilization or other biological functions. In a mammalian model of human otitis media, we determined that Fur was critical for bacterial persistence, indicating an important role for Fur-mediated iron homeostasis in disease progression. These data provide a profile of genes regulated by Fur in NTHi and likely identify additional regulatory pathways involved in iron utilization. Identification of such pathways will increase our understanding of how this pathogen can persist within host microenvironments, as a common commensal and, importantly, as a pathogen with significant clinical impact.

The Haemophilus influenzae Sap transporter mediates bacterium-epithelial cell homeostasis.

Nontypeable Haemophilus influenzae (NTHI) is a commensal inhabitant of the human nasopharynx and a causative agent of otitis media and other diseases of the upper and lower human airway. During colonization within the host, NTHI must acquire essential nutrients and evade immune attack. We previously demonstrated that the NTHI Sap transporter, an inner membrane protein complex, mediates resistance to antimicrobial peptides and is required for heme homeostasis. We hypothesized that Sap transporter functions are critical for NTHI interaction with the host epithelium and establishment of colonization. Thus, we cocultured the parent or the sapA mutant on polarized epithelial cells grown at an air-liquid interface, as a physiological model of NTHI colonization, to determine the contribution of the Sap transporter to bacterium-host cell interactions. Although SapA-deficient NTHI was less adherent to epithelial cells, we observed a significant increase in invasive bacteria compared to the parent strain. Upon internalization, the sapA mutant appeared free in the cytoplasm, whereas the parent strain was primarily found in endosomes, indicating differential subcellular trafficking. Additionally, we observed reduced inflammatory cytokine production by the epithelium in response to the sapA mutant strain compared to the parental strain. Furthermore, chinchilla middle ears challenged with the sapA mutant demonstrated a decrease in disease severity compared to ears challenged with the parental strain. Collectively, our data suggest that NTHI senses host environmental cues via Sap transporter function to mediate interaction with host epithelial cells. Epithelial cell invasion and modulation of host inflammatory cytokine responses may promote NTHI colonization and access to essential nutrients.

SapF-mediated heme-iron utilization enhances persistence and coordinates biofilm architecture of Haemophilus.

Non-typeable Haemophilus influenzae (NTHI) is a common commensal bacterium that resides in the human upper respiratory tract of healthy individuals. NTHI is also a known causative agent of multiple diseases including sinusitis, otitis media, as well as exacerbates disease severity of patients with cystic fibrosis and chronic obstructive pulmonary disease. We have previously shown that the Sap transporter mediates resistance to host antimicrobial peptides (AMPs) and import of the iron-containing compound heme. Here, we analyzed the contribution of the Sap structural ATPase protein, SapF, in these essential functions. In contrast to SapD, SapF was dispensable for NTHI survival when exposed to AMPs in vitro. SapF was responsible for heme utilization and recovery of depleted internal heme-iron stores. Further, a loss of SapF resulted in morphological plasticity and enhanced community development and biofilm architecture, suggesting the potential role of heme-iron availability in coordinating the complexity of NTHI biofilm architecture. SapF was required for colonization of the nasopharynx and acute infection of the middle ear, as SapF deficiency correlated with a statistically significant decrease in NTHI persistence in vivo. These data suggest that SapF is required for proper heme utilization which directly impacts NTHI survival. Thus, these studies further support a role for the Sap complex in the transport of multiple substrates and further defines substrate specificity for the two ATPase subunits. Given the multiple essential functions provided by the Sap transporter, this complex could prove to be an effective therapeutic target for the treatment of NTHI diseases.