We report a case of a 22-year-old male who was previously treated for asthma from childhood, and his repeated respiratory infections prompted the physician to start antitubercular therapy (ATT) thrice, suspecting pulmonary tuberculosis despite being sputum acid-fast bacillus (AFB) negative every time. Diagnosis of Kartagener syndrome (autosomal recessive inheritance having a triad of bronchiectasis, chronic sinusitis, situs inversus, and strongly associated with infertility) was made in this case at our tertiary care referral hospital, but it was already too late when he presented with life-threatening bilateral pneumonia, bilateral pleural effusion with type II respiratory failure, and associated cystitis warranting mechanical ventilation, and he succumbed because of extremely and irreversibly damaged lungs.

Primary ciliary dyskinesia (PCD) is a rare, congenital condition in which impaired ciliary function leads to bronchiectasis and progressive lung function decline. Bronchiectasis development is believed to involve infection and inflammation but is incompletely understood. Macrophages play a central role in cellular immune response, contributing to both pathogen clearance and immunoregulation. Depending on local stimuli, macrophages are polarized towards pro-inflammatory (M1) or pro-resolution/phagocytic (M2) phenotypes. This study aims to investigate the effects of PCD sputum on macrophage polarization. Sputum from 27 individuals with PCD and seven healthy controls were used to stimulate healthy monocyte-derived macrophages. Macrophage polarization was determined by surface markers, phagocytic ability and cytokine production using flow cytometry and immunoassays. Macrophages stimulated with PCD sputum exhibited enhanced phagocytosis (MFI 194268 vs. 58235, p = 0.0002), increased expression of M2-associated surface markers CD163, CD206 and CD16, and reduced secretion of proinflammatory cytokines IL-6 (10.38 vs. 113.22 pg/ml, p = 0.0013) and IL-1β (0.75 vs. 3.60 pg/ml, p < 0.0001). Concurrently, expressions of M1-associated surface markers CD40 and CD80 were reduced. PCD sputum induced a phagocytosis prone, M2-like phenotype in healthy macrophages.

Primary ciliary dyskinesia (PCD), a rare ciliopathy disorder, is caused by variants in multiple genes, with DNAH5 being one of the most frequently implicated. However, the precise relationship between variant type or location in the DNAH5 gene and the clinical heterogeneity remains elusive. The present systematic review aims to provide critical insights into the impact of the molecular nature of DNAH5 variants on PCD phenotypes. We enrolled all reported cases of PCD with biallelic pathogenic variants in the DNAH5 gene to date, and evaluated genotype-phenotype correlations in these patients, employing truncating (TV) and missense (MV) variant-carrying as grouping criteria. A total of 323 PCD patients with the DNAH5 variants were included, with 14.55% of these patients were diagnosed as Kartagener syndrome. Pediatric and adult patients exhibited distinct clinical features, including varying incidences of bronchiectasis, infertility, neonatal respiratory distress (NRD), ciliary ultrastructural defects distributions, and lung function (all p < 0.05). With regard to mutational patterns, truncating variants in DNAH5 were clustered in the 1200-3200 amino acid region, and were more prevalent in children compared to adult (p < 0.0001). Most missense variants are clustering in the linker, AAA + ATPase and AAA-lid domains. The most frequently observed mutation, c.10815delT, was prevalent in Europe and America, whereas c.8030G > A was more common in China and Asia. In terms of genotype-phenotype correlations, individuals with the TV/TV genotype exhibited a higher proportion of NRD and earlier onset compared to those with MV-carrying genotypes, both in overall population and in pediatric patients (all p < 0.05). Patients with the TV/TV genotype exhibited worse lung function compared to those with MV-carrying genotypes. The study underscores the broad mutational spectrum and high phenotypic heterogenicity in DNAH5-related PCD patients. The presence of biallelic truncating variants may predispose patients to earlier disease onset and poorer lung function.

Kartagener's syndrome is a rare subset of primary ciliary dyskinesia, a genetically heterogeneous disorder characterised by chronic sinusitis, bronchiectasis, and situs inversus. To our knowledge, the association of this syndrome with coarctation of the aorta (CoAo) and pulmonary hypertension (PH) has not been previously reported. We report the case of a 17-year-old female patient with situs inversus and CoAo surgically corrected at two months of age. At 12 years old, she developed a chronic cough, nasal congestion, and an estimated pulmonary artery systolic pressure (PASP) of 70 mmHg on echocardiography. Cardiac catheterisation revealed a pulmonary artery pressure of 58/10/24 mmHg with no gradient at the aortic isthmus. Thoracic CT scan demonstrated multiple bronchiectasis in the upper lobes bilaterally, despite normal pulmonary spirometry, plethysmography, and 24-hour oximetry. Genetic testing identified a pathogenic variant and a variant of uncertain significance of the DNAH5 gene, associated with primary ciliary dyskinesia. The patient was diagnosed with Kartagener's syndrome with PH and was started on inhaled glucocorticoids and chest physiotherapy. No episodes of pneumonia or acute bronchiectasis exacerbations were recorded. Annual lung function tests remained normal, and semiannual echocardiograms showed stable findings. A follow-up thoracic CT scan at 16 years of age revealed no progression of lung disease. At 16 years old, the patient developed significant physical activity limitation. Echocardiographic evaluation demonstrated right ventricular dilatation with reduced longitudinal function (TAPSE 15 mm, Z-score 4.4), suprasystemic PASP (120 mmHg), an eccentricity index of 2.3, normal left ventricular function, moderate pericardial effusion, and an NT-ProBNP level of 2292 pg/mL. Combined therapy targeting PH was initiated, including an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, diuretics, and supplemental oxygen therapy. Significant clinical improvement was observed (WHO functional class IIIa to I), along with echocardiographic improvement (PASP reduced to 80 mmHg, TAPSE increased to 16 mm, resolution of pericardial effusion), and a marked decrease in NT-proBNP (171 pg/mL). The rapid progression of PH in this patient, despite normal lung function and unremarkable CT scan findings, is atypical for PH associated with lung disease. Extensive investigation for alternative causes of PH, including genetic testing, yielded negative results. A more aggressive treatment strategy for PH is currently being pursued.

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator, CFTR, an epithelial anion transport protein, responsible for, inter alia, sputum viscoelasticity in the lung. We previously identified the TNF receptor superfamily 1A TNFRSF1A (TNFR1) as a genetic modifier of CFTR function and disease severity in the CF twin and sibling study population. We aimed to replicate our findings in independent cohorts, assess the role of TNFR1 for patient survival and identify functional changes associated with TNFR1 polymorphisms. We incorporated data from three independent long-term mono- and multicentric cohorts of people with cystic fibrosis (pwCF) to confirm the previously described association of TNFR1 with CFTR function and to extend our study to include survival data for our local cohort and a pan-European cohort of pwCF. We studied TNFR1 transcripts obtained from primary airway epithelia grown as air-liquid interface cultures to address possible mechanisms involved in up-stream and down-stream effects of TNFR1. Survival differed by more than a decade when comparing carriers of contrasting TNFR1 genotypes among unrelated pwCF as well as among CF siblings pairs. The presence of the TNFR1 transcript variant TNFR1delEx2 in primary airway epithelia was associated with TNFR1 genotype. The association of the TNFR1 transcript variant TNFR1delEx2 associates with the TNFR1 genotype, possibly mediating the genotype-survival association we found regarding TNFR1 genotype and patient survival in cystic fibrosis. Supported by the German Ministry for Education and Research (BMBF) (82DZL009B1 to MAM and 82DZL002A1, to GH, BT, AMD, FS) and the Mukoviszidose Institut gGmbH (MI-2002, to LN, AMD, FS).