The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no “gold standard” reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.

Michel Georges and colleagues identify a founder mutation in CCDC39 associated with primary ciliary dyskinesia in Old English Sheepdogs. They further show that mutations in human CCDC39 cause a similar phenotype and that CCDC39 is required for the assembly of inner dynein arms and the dynein regulatory complex. Primary ciliary dyskinesia (PCD) is an inherited disorder characterized by recurrent infections of the upper and lower respiratory tract, reduced fertility in males and situs inversus in about 50% of affected individuals (Kartagener syndrome). It is caused by motility defects in the respiratory cilia that are responsible for airway clearance, the flagella that propel sperm cells and the nodal monocilia that determine left-right asymmetry1. Recessive mutations that cause PCD have been identified in genes encoding components of the outer dynein arms, radial spokes and cytoplasmic pre-assembly factors of axonemal dyneins, but these mutations account for only about 50% of cases of PCD. We exploited the unique properties of dog populations to positionally clone a new PCD gene, CCDC39. We found that loss-of-function mutations in the human ortholog underlie a substantial fraction of PCD cases with axonemal disorganization and abnormal ciliary beating. Functional analyses indicated that CCDC39 localizes to ciliary axonemes and is essential for assembly of inner dynein arms and the dynein regulatory complex.

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins.

Non-intubated critically ill patients are often treated by high-flow oxygen for acute respiratory failure. There is no current recommendation for humidification of oxygen devices. We conducted a prospective randomized trial with a final crossover period to compare nasal airway caliber and respiratory comfort in patients with acute hypoxemic respiratory failure receiving either standard oxygen therapy with no humidification or heated and humidified high-flow oxygen therapy (HHFO₂) in a medical ICU. Nasal airway caliber was measured using acoustic rhinometry at baseline, after 4 and 24 hours (H4 and H24), and 4 hours after crossover (H28). Dryness of the nose, mouth, and throat was auto-evaluated and assessed blindly by an otorhinolaryngologist. After the crossover, the subjects were asked which system they preferred. Thirty subjects completed the protocol and were analyzed. Baseline median oxygen flow was 9 and 12 L/min in the standard and HHFO₂ groups, respectively (P = .21). Acoustic rhinometry measurements showed no difference between the 2 systems. The dryness score was significantly lower in the HHFO₂ group at H4 (2 vs 6, P = .007) and H24 (0 vs 8, P = .004). During the crossover period, dryness increased promptly after switching to standard oxygen and decreased after switching to HHFO₂ (P = .008). Sixteen subjects (53%) preferred HHFO₂ (P = .01), especially those who required the highest flow of oxygen at admission (P = .05). Upper airway caliber was not significantly modified by HHFO₂, compared to standard oxygen therapy, but HHFO₂ significantly reduced discomfort in critically ill patients with respiratory failure. The system is usually preferred over standard oxygen therapy.