Cystic fibrosis and CFTR-related disorder with electrolyte imbalance at diagnosis: clinical features and outcome in an Italian cohort.

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2%) were diagnosed with CF, and 11 received a CFTR-Related Disorder (CFTR-RD) diagnostic label. Twenty-three (85.1%) out of the 27 subjects who underwent CF neonatal screening (NBS) resulted falsely negative. After a mean observational period of 11.5 years, most of subjects had a mild pulmonary phenotype, pancreatic sufficiency, and rarely CF-related complications. Four CFTR-RD changed to a CF diagnosis during the study period, resulting in 86 (92.4%) subjects classified as CF. CONCLUSIONS:  Most CF patients presenting with isolated HMA have a mild course of disease and rarely CF-related complications. WHAT IS KNOWN: • Isolated episode of hypoelectrolytemia with metabolic alkalosis is a well-known onset symptom of Cystic Fibrosis in infancy. • There is limited information available on the clinical data and outcomes of individuals with Cystic Fibrosis who present with electrolyte imbalance at diagnosis. WHAT IS NEW: • Most patients with Cystic Fibrosis presenting with isolated hypoelectrolytemia and metabolic alkalosis have a mild course of disease and rarely CF-related complications. • Electrolyte imbalance at diagnosis of Cystic Fibrosis is a common symptom in children not screened for CF at birth, or in those who received a false negative result from newborn screening.

Different management approaches and outcome for infants with an inconclusive diagnosis following newborn screening for cystic fibrosis (CRMS/CFSPID) and Pseudomonas aeruginosa isolation.

INTRODUCTION: Evidence is currently lacking to guide the management of cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome CF screen-positive inconclusive diagnosis (CRMS/CFSPID) with Pseudomonas aeruginosa (Pa)-positive respiratory culture. This study assessed the clinical data, management, and outcomes of an Italian cohort of CRMS/CFSPID infants with Pa isolated from their airways. METHODS: Data of Pa-positive CRMS/CFSPID infants born between January 2011 and August 2018 and followed at five CF Italian centres were retrospectively extracted. Further data were collected until June 2021 to assess outcomes, prevalence of subjects treated with antimicrobials, and treatment type and duration. RESULTS: Forty-three asymptomatic CRMS/CFSPID patients (median age on 30 June 2021, 82 months; interquartile range [IQR], 63-98 months) with at least one positive airway culture for non-mucoid Pa (median age at first isolation, 18.7 months; IQR, 7-25 months) were enrolled. Of them, 24 (55.8%) underwent anti-Pa therapy. Pa clearance occurred in 22 (91.6%) of 24 patients versus spontaneous clearance in 16 of 19 (84.2%) untreated patients (chi-square, 0.5737; p = 0.44878). After a median follow-up of 6.2 years (IQR, 3.0-9.9), 7 (16.3%) were diagnosed with CF after a pathological sweat test (median age, 43 months; IQR, 28-77 months), 3 (7%) developed recurrent pancreatitis or isolated bronchiectasis consistent with CFTR-related disorder, and the CRMS/CFSPID classification remained in 33 (76.7%). CONCLUSIONS: Pa detection frequently occurs in asymptomatic infants with CRMS/CFSPID but tends to clear spontaneously. More studies are needed to determine if Pa isolation can predict evolution.

Clinical outcomes of a large cohort of individuals with the F508del/5T;TG12 CFTR genotype.

BACKGROUND: In recent years, patients with cystic fibrosis (CF) conductance regulator (CFTR) variant poly(T) sequences have been increasingly reported with a wide spectrum of clinical severity. We describe the long-term clinical outcomes and progression to a CF diagnosis over time in a large Italian cohort of patients carrying the CFTR F508del/5T;TG12 genotype. METHODS: A retrospective analysis of subjects from 10 CF centres in Italy with the F508del/5T;TG12 genotype was performed. Demographic, clinical, microbiological, and biochemical data, as well as information about the follow-ups and complications of the enroled patients, were collected. RESULTS: A total of 129 subjects (54 females; median age: 15.0 years, range: 0-58 years; 59 older than 18 years) were included. In terms of initial diagnoses, 30 were CF (23.3%), 41 were CFTR-related disorder (CFTR-RD) (31.7%), and 58 were CF transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID) (45.0%). After a median follow-up of 6.7 years (range 0.2-25 years), 15 patients progressed to CF, bringing the total number of CF diagnoses to 45/129 (34.9%). Most of these patients had mild lung diseases with pancreatic sufficiency and a low prevalence of CF-related complications. CONCLUSIONS: At the end of the study, 34.9% of subjects with the CFTR F508del/5T;TG12 genotype were diagnosed with CF. We suggest including patients with the F508del/5T;TG12 genotype in long-term follow-ups.

Outcomes of early repeat sweat testing in infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/CF screen-positive, inconclusive diagnosis.

BACKGROUND: Reaching early and definitive diagnosis in infants with cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS)/CF screen-positive, inconclusive diagnosis (CFSPID) is a priority of all CF newborn screening programs. Currently, sweat testing (ST) is the gold standard for CF diagnosis or exclusion. We assessed outcomes in a cohort of Italian CRMS/CFSPID infants who underwent repeat ST in the 1st year of life. METHODS: This multicentre, prospective study analysed clinical data and outcomes in CRMS/CFSPID infants born between September 1, 2018, and December 31, 2019, and followed until June 30, 2020. All subjects underwent CF transmembrane conductance regulator (CFTR) gene sequencing and the search for CFTR macrodeletions/macroduplications, and repeat ST in the 1st year of life. RESULTS: Fifty subjects (median age at end of follow-up, 16 months [range, 7-21 months]) were enrolled. Forty-one (82%) had the first sweat chloride (SC) in the intermediate range. During follow up, 150 STs were performed (range, 1-7/infant). After a median follow-up of 8.5 months (range, 1-16.2 months), 11 (22%) subjects were definitively diagnosed as follows: CF (n = 2 [4%]) at 2 and 5 months, respectively; healthy carrier (n = 8 [16%]), at a median age of 4 months (range, 2-8 months); and healthy (n = 1 [2%]) at 2 months of age. Inconclusive diagnosis remained in 39 (78%) infants. CONCLUSIONS: Early repeat ST in the 1st year of life can shorten the time to definitive diagnosis in screening positive subjects with initial SC levels in the intermediate range.

A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres.

OBJECTIVE: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres. METHODS: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected. RESULTS: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%). CONCLUSIONS: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.

Remote support by multidisciplinary teams: A crucial means to cope with the psychological impact of the SARS-COV-2 pandemic on patients with cystic fibrosis and inflammatory bowel disease in Lombardia.

BACKGROUND: During Coronavirus Disease 2019 (COVID-19) outbreak in Lombardia, people were recommended to avoid visiting emergency departments and attending routine clinic visits. In this context, it was necessary to understand the psychological reactions of patients with chronic diseases. We evaluated the psychological effects on patients with chronic respiratory conditions and inflammatory bowel disease (IBD) through the analysis of their spontaneous contacts with their referral centres. METHODS: Cross-sectional study was conducted from February 23 to April 27, 2020 in patients, or their parents, who contacted their multidisciplinary teams (MDT). E-mails and phone calls directed to the MDT of the centre for cystic fibrosis (CF) in Milano and for paediatric IBD in Bergamo, were categorised according to their contents as information on routine disease management, updates on the patient's health status, COVID-19 news monitoring, empathy towards health professionals, positive feedback and concern of contagion during the emergency. RESULTS: One thousand eight hundred and sixteen contacts were collected during the study period. In Milano, where the majority of patients were affected by CF, 88.7% contacted health professionals by e-mail, with paediatricians receiving the largest volume of emails and phone calls compared with other professionals (P< .001). Compared with Milano, the centre for IBD in Bergamo recorded more expression of empathy towards health professionals and thanks for their activity in the COVID-19 emergency (52.4% vs 12.7%, P< .001), as well as positive feedback (64.3% vs 2.7%, P = .003). CONCLUSION: One of the most important lessons we can learn from COVID-19 is that it is not the trauma itself that can cause psychological consequences but rather the level of balance, or imbalance, between fragility and resources. To feel safe, people need to be able to count on the help of those who represent a bulwark against the threat. This is the role played, even remotely, by health professionals.

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

BACKGROUND: There are no predictive factors of evolution of cystic fibrosis (CF) screen positive inconclusive diagnosis subjects (CFSPIDs). AIM: to define the role of the second CFTR variant as a predictive factor of disease evolution in CFSPIDs carrying the D1152H variant. METHODS: We retrospectively evaluated clinical characteristics and outcome of CFSPIDs carrying the D1152H variant followed at five Italian CF centers. CFSPIDs were divided in two groups: Group A: compound heterozygous for D1152H and a CF-causing variant; Group B: compound heterozygous for D1152H and a: (i) non CF-causing variant, (ii) variant with varying clinical consequences, or (iii) variant with unknown significance. The variants were classified according to CFTR2 mutation database. RESULTS: We enrolled 43 CFSPIDs with at least one D1152H variant: 28 (65.1%) were classified in the group A, and 15 (34.9%) in the Group B. CFSPIDs of group A had the first IRT significantly higher compared to those of group B (p < 0.05) and had a more severe clinical outcome during the follow-up. At the end of the study period, after a mean follow-up of 40.6 months (range 6-91.6), 4 (9.3%) out of 43 CFSPIDs progressed to CFTR-RD or CF. All these subjects were in the group A. CONCLUSIONS: The genetic profile could help predict the risk of disease evolution in CFSPIDs carrying D1152H, revealing the subjects that need a more frequent follow-up.

Night Blindness in Cystic Fibrosis: The Key Role of Vitamin A in the Digestive System.

Vitamin A is a fundamental micronutrient that regulates various cellular patterns. Vitamin A deficiency (VAT) is a worldwide problem and the primary cause of nocturnal blindness especially in low income countries. Cystic fibrosis (CF) is a known risk factor of VAD because of liposoluble vitamin malabsorption due to pancreatic insufficiency. We describe a case of a 9-year-old girl who experienced recurrent episodes of nocturnal blindness due to profound VAD. This little girl is paradigmatic for the explanation of the key role of the gut-liver axis in vitamin A metabolism. She presents with meconium ileus at birth, requiring intestinal resection that led to a transient intestinal failure with parenteral nutrition need. In addition, she suffered from cholestatic liver disease due to CF and intestinal failure-associated liver disease. The interaction of pancreatic function, intestinal absorption and liver storage is fundamental for the correct metabolism of vitamin A.

Successful ceftazidime-avibactam treatment of post-surgery Burkholderia multivorans genomovar II bacteremia and brain abscesses in a young lung transplanted woman with cystic fibrosis.

Burkholderia cepacia complex (Bcc) includes several phenotypically similar but genotypically distinct gram-negative bacteria (GNB) that can colonize the respiratory tract of Cystic Fibrosis (CF) patients. Pathogens are difficult to treat due to intrinsic resistance to multiple antibiotics and are associated to a more rapid decline in lung function and to increased mortality, particularly after lung transplantation. For all these reasons, chronic infection by Burkholderia (B) cenocepacia is presently considered a relative or absolute contraindication in almost all lung transplant centres. We report the case of a young adult CF patient chronically colonized by B multivorans genomovar II, with diabetes and end-stage renal disease treated with renal replacement therapy: a few months after lung transplantation, she developed post-surgery B multivorans bacteremia and multiple brain abscesses. This severe infection did not improve despite multiple standard antibiotic regimen. The introduction of ceftazidime-avibactam, a new ß-lactam/ ß-lactamase inhibitor combination resulted in clinical recovery and in radiological and biochemical improvement.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in two young children: the importance of an early diagnosis.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a serious life-treating condition characterized by skin eruption, fever, haematologic abnormalities, and multi-organ involvement that can be fatal if unrecognized, especially in patients with liver failure. Diagnosis may be difficult because it is rarely described in children and can mimic many different conditions. CASE PRESENTATION: We report two cases of DRESS syndrome due to prolonged antibiotic treatment in young children in whom recovery occurred following different therapeutic approaches. A previously healthy 5-year-old boy had been receiving intravenous vancomycin for right wrist and left elbow osteomyelitis and developed DRESS syndrome on day 30. The patient achieved a complete resolution of all symptoms with pulse methylprednisolone followed by oral prednisone. A 4-year-old girl with cystic fibrosis, pancreatic insufficiency, chronic pulmonary colonization by Gram-positive bacteria admitted for pulmonary exacerbation was treated with intravenous piperacillin-tazobactam and tobramycin. After 14 days of treatment, she developed DRESS syndrome: antibiotic treatment was therefore stopped, and without any further therapy, a progressive resolution of the patient's clinical features was observed within 7 days, while the normalization of laboratory abnormalities was achieved at 14 days. CONCLUSIONS: Our cases highlight that paediatricians should be aware of the clinical presentations of and therapeutic approaches for DRESS syndrome, especially in children receiving long-term antibiotic treatment. The removal of the offending drug is crucial and may be the only life-saving measure. In more aggressive cases, corticosteroid or other immunosuppressive drugs should be considered to achieve the best outcome.

Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease. OBJECTIVE: To assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF. METHODS: In a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15 years (range 5-26 yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N=14) or hyaluronate alone (N=13) for 14 days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms. RESULTS: The formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects. CONCLUSIONS: The present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. TRIAL REGISTRATION NUMBER: EudraCT 2007-003628-39.

Insulin secretion, nutritional status and respiratory function in cystic fibrosis patients with normal glucose tolerance.

BACKGROUND & AIMS: Impaired growth and nutritional status in CF may be related to progressive insulin deficiency before CF-Related Diabetes has established. Aim of this study was to analyse the association of circulating insulin with nutritional status and lung function in CF patients with normal glucose tolerance (NGT). METHODS: We performed OGTT in 152 consecutive CF patients aged 8-20 years: 115 of them had NGT and were included in the study. Areas under the curves (AUC) of glucose, insulin and c-peptide after 120 min were calculated. Quartiles (Q) of increasing fasting insulin (fINS-Q) and c-peptide (fCP-Q) levels were calculated in CF patients. Respiratory function parameters (FEV1, FVC), Standard Deviation Scores (SDS) of height, weight and BMI were compared between Q1 and the three higher Q. Multiple regression analysis was used to analyse the association of fasting insulin, c-peptide or OGTT derived indices with nutritional or respiratory parameters. RESULTS: Compared to patients in fINS-Q4 or fCP-Q4, those in fINS-Q1 or in fCP-Q1 respectively showed lower levels of insulin AUC or c-peptide AUC (both P < 0.0001), weight-SDS (P = 0.013, P = 0.007), BMI-SDS (P = 0.010, P = 0.002), FEV1 (P = 0.076, P = 0.013) and FVC (P = 0.101, P = 0.009). Age- and gender-adjusted regression analysis showed significant associations of fINS and fCP with SDS of BMI (P = 0.023 and P = 0.001 respectively), fCP was significant associated with FEV1 (P = 0.01). AUC insulin/AUC glucose ratio (P < 0.0001) and AUC c-peptide/AUC glucose ratio (P = 0.0001) were significantly associated with FEV1. CONCLUSIONS: Insulin deficiency in CF patients with NGT has a significant impact on clinical outcomes.

A wide methodological approach to identify a large duplication in CFTR gene in a CF patient uncharacterised by sequencing analysis.

BACKGROUND: PCR-based diagnostic procedures are not able to characterise 6% of CF alleles. Recently, the application of array-CGH and of CFTR mRNA analysis has allowed the identification of new copy number mutations and splicing defects, that account for 2% and 13% of CF alleles, respectively, in the Italian population. METHODS: Here, we report the characterisation of a large duplication in CFTR gene through different methods: MLPA assay, RT-PCR and high-resolution array-CGH. RESULTS: We identified a large duplication, involving exons 6b-16, in a patient heterozygous for F508del mutation. This duplication produces an abnormal transcript with an out of frame addition of 2244 nucleotides and leads to the insertion of 8 amino-acid residues in the protein, followed by a stop codon. CONCLUSIONS: We propose a wide methodological approach based on MLPA assay, RT-PCR and high-resolution array-CGH to routinely analyse CF patients uncharacterised for one or both CFTR alleles.

A novel donor splice site characterized by CFTR mRNA analysis induces a new pseudo-exon in CF patients.

BACKGROUND: The CFTR gene is tightly regulated and differentially expressed in many mucosal epithelial cell types. There is evidence of an increasing number of genomic variations in the intronic regions influencing mRNA splicing, and also the level of normal CFTR transcript. METHODS: In the present study, we investigate the molecular defect by RT-PCR analyzing the mRNA of 25 cystic fibrosis (CF) patients in whom only one or no CF allele had been identified after DNA analysis (of all the exons of the CFTR gene). RESULTS: mRNA analysis led to the detection of a cryptic exon in two patients: the new exon is a 104 bp insertion between exons 10 and 11 and is caused by a new point mutation c.1584+18672 bp A>G (http://www.hgvs.org/mutnomen/) discovered in intron 10; moreover, they showed the absence of exon 9 skipping. CONCLUSIONS: Our results confirm the utility of RNA analysis in discovering new mutations and in investigating their effect on normal splicing processes.

Clinical and economic impact of influenza vaccination on healthy children aged 2-5 years.

This paper reports the data concerning the net economic cost savings attributable to influenza vaccination in healthy children aged 2-5 years, and may be useful when deciding the best recommendations for the use of influenza vaccine in pediatrics. A total of 303 previously unprimed healthy children aged 2-5 years (163 males; mean age+/-S.D.: 3.22+/-2.43 years) were prospectively, blindly randomised in a 2:1 ratio to receive two doses of an inactivated, trivalent, virosome-formulated subunit influenza vaccine (Inflexal V, Berna Biotech, Berne, Switzerland) or no vaccination. The results show that influenza vaccination of healthy children aged 2-5 years substantially reduces influenza-like illnesses and related costs in the children themselves and their families. However, larger and longer running study spanning multiple seasons may be warranted before suggesting the universal vaccination of this group of subjects.

Differences in nasopharyngeal bacterial flora in children with nonsevere recurrent acute otitis media and chronic otitis media with effusion: implications for management.

BACKGROUND: The interactions between nasopharyngeal flora and the individual entities covered by the broad term otitis media have not been completely elucidated. We investigated in infants and children ages 6 months to 7 years with nonsevere recurrent acute otitis media (rAOM) or with chronic otitis media with effusion (cOME): (1) the nasopharyngeal carriage rate and bacterial density of respiratory pathogens and alpha-hemolytic streptococci in comparison with healthy children; (2) the resistance pattern of respiratory pathogens; and (3) the relationship between the type of nasopharyngeal colonization and long term outcome. METHODS: Nasopharyngeal cultures were obtained from 85 children with rAOM,113 children with cOME and 55 controls. A semiquantitative analysis was used in the reading of cultures. A 12-week follow-up without treatment was planned. RESULTS: The carrier rate of respiratory pathogens was significantly greater in cOME (70%) than in rAOM (45%) (P = 0.0006) or controls (31%) (P < 0.0001). Similarly colonization density was significantly greater in cOME than in rAOM. The carriage rate and the colonization density of alpha-hemolytic streptococci were significantly lower in rAOM than in cOME or controls. The incidence of resistant (R) strains was greater in rAOM (Streptococcus pneumoniae penicillin-R, 24%; macrolide-R, 64%; Haemophilus influenzae amoxicillin-R, 24%) compared with cOME (S. pneumoniae penicillin-R,18%; macrolide-R, 44%; H. influenzae amoxicillin-R, 5%) or controls (S. pneumoniae penicillin-R, 8%; macrolide-R, 23%; H. influenzae amoxicillin-R, 10%). During the follow-up period persistence of OME and occurrence of AOM were greater among carriers of respiratory pathogens at baseline. CONCLUSIONS: There are substantial differences in nasopharyngeal flora between children with nonsevere rAOM and children with cOME. The results of nasopharyngeal cultures should be taken into account to avoid treatment with drugs that are ineffective and likely to select resistant organisms.

Cytokine secretion in children with acute Mycoplasma pneumoniae infection and wheeze.

The aim of this study was to evaluate cytokine secretion in children with acute Mycoplasma pneumoniae infection and wheeze. We studied 25 patients aged 2-14 years with an acute episode of wheezing (15 with acute M. pneumoniae infection) and 16 healthy controls of similar gender and age (8 with laboratory evidence of asymptomatic acute M. pneumoniae infection). Serum interleukin (IL)-2, interferon (IFN)-gamma, IL-4, and IL-5 concentrations were measured in samples obtained at enrollment, using enzyme-linked immunosorbent assay kits. In the presence of wheezing, IL-5 concentrations were significantly higher in subjects with acute M. pneumoniae infection (33.415 +/- 22.138 pg/mL) than in those without such infection (2.320 +/- 1.846 pg/mL, P < 0.0001). The children with acute M. pneumoniae infection and wheeze had higher IL-5 concentrations (33.415+/-22.138 pg/mL) than those with asymptomatic acute infection and without wheeze (1.740 +/- 2.299 pg/mL, P < 0.0001). No significant between-group differences were observed in terms of IL-2, IFN-gamma, or IL-4 levels, or the prevalence of atopy. Our results show that children with wheezing and acute M. pneumoniae infection have a specific cytokine profile characterized by a significant increase in serum levels of IL-5. This immune response may be important for understanding the pathophysiological mechanisms by which this pathogen contributes to the development of wheeze-related symptoms, and for identifying new treatment strategies.