The Role of Serotonin Transporter in Human Lung Development and in Neonatal Lung Disorders.

Introduction. Failure of the vascular pulmonary remodeling at birth often manifests as pulmonary hypertension (PHT) and is associated with a variety of neonatal lung disorders including a uniformly fatal developmental disorder known as alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV). Serum serotonin regulation has been linked to pulmonary vascular function and disease, and serotonin transporter (SERT) is thought to be one of the key regulators in these processes. We sought to find evidence of a role that SERT plays in the neonatal respiratory adaptation process and in the pathomechanism of ACD/MPV. Methods. We used histology and immunohistochemistry to determine the timetable of SERT protein expression in normal human fetal and postnatal lungs and in cases of newborn and childhood PHT of varied etiology. In addition, we tested for a SERT gene promoter defect in ACD/MPV patients. Results. We found that SERT protein expression begins at 30 weeks of gestation, increases to term, and stays high postnatally. ACD/MPV patients had diminished SERT expression without SERT promoter alteration. Conclusion. We concluded that SERT/serotonin pathway is crucial in the process of pulmonary vascular remodeling/adaptation at birth and plays a key role in the pathobiology of ACD/MPV.

Blood Transfusions in Dogs and Cats Receiving Hemodialysis: 230 Cases (June 1997-September 2012).

BACKGROUND: Multiple factors exist that contribute to anemia in dogs and cats receiving hemodialysis, can necessitate transfusion. OBJECTIVES: To describe blood product usage in dogs and cats with acute and chronic kidney disease that were treated with intermittent hemodialysis to determine risk factors associated with the requirement for blood product transfusion. ANIMALS: 83 cats and 147 dogs undergoing renal replacement therapy at the Animal Medical Center for acute or chronic kidney disease. METHODS: Retrospective medical record review of all dogs and cats receiving renal replacement therapy for kidney disease, from June 1997 through September 2012. RESULTS: Blood products (whole blood, packed RBCs, or stromal-free hemoglobin) were administered to 87% of cats and 32% of dogs. The number of dialysis treatments was associated with the requirement for transfusion in cats (adjusted OR 2.21, 95% CI 1.13, 4.32), but not in dogs (adjusted OR 0.98, 95% CI 0.95, 1.03). Administration of a blood product was associated with a higher likelihood of death in dogs (OR 3.198, 95% CI 1.352, 7.565; P = .0098), but not in cats (OR 1.527, 95% CI 0.5404, 4.317, P = .2). CONCLUSIONS AND CLINICAL IMPORTANCE: Veterinary hospitals with a hemodialysis unit should have reliable and rapid access to safe blood products in order to meet the needs of dogs and cats receiving dialysis.

Hypothermia in Uremic Dogs and Cats.

BACKGROUND: The prevalence of uremic hypothermia (UH) and the effects of improving uremia on body temperature have not been determined in veterinary patients. OBJECTIVES: To determine the prevalence of UH and correlations between uremia and body temperature in patients undergoing intermittent hemodialysis (IHD). ANIMALS: Uremic dogs (n = 122) and cats (n = 79) treated by IHD at the Bobst Hospital of the Animal Medical Center from 1997 to 2013. METHODS: Retrospective review of medical records. RESULTS: The prevalence of hypothermia was 38% in azotemic cats and 20.5% in azotemic dogs. Statistically significant temperature differences were observed between uremic and nonuremic dogs (nonuremic: mean, 100.8°F; range, 91.2-109.5°F; uremic: mean, 99.9°F; range, 95.6-103.8°F; P < .0001) and cats (nonuremic: mean, 100.6°F; range, 94.0-103.8°F; uremic: mean, 99.3°F; range, 92.3-103.4°F; P < .0001). In dog dialysis patients, significant models included (1) timing (pre-dialysis versus post-dialysis) with weight class (small [P < .0001], medium [P = .016], and large breed [P = .033] dogs), (2) timing with serum creatinine concentration (P = .021), and (3) timing with BUN concentration (P < .0001). In cat dialysis patients, there was a significant interaction between timing and weight as a categorical variable (<5 kg and ≥5 kg). CONCLUSIONS AND CLINICAL IMPORTANCE: Uremic hypothermia appears to be a clinical phenomenon that occurs in cats and dogs. Uremic patients are hypothermic compared to ill nonuremic patients and body temperatures increase when uremia is corrected with IHD in dogs and in cats >5 kg. In cats, UH seems to be a more prevalent phenomenon driven by uremia. Uremic hypothermia does occur in dogs, but body weight is a more important predictor of body temperature.

Validation of a Clinical Scoring System for Outcome Prediction in Dogs with Acute Kidney Injury Managed by Hemodialysis.

BACKGROUND: A scoring system for outcome prediction in dogs with acute kidney injury (AKI) recently has been developed but has not been validated. HYPOTHESIS: The scoring system previously developed for outcome prediction will accurately predict outcome in a validation cohort of dogs with AKI managed with hemodialysis. ANIMALS: One hundred fifteen client-owned dogs with AKI. METHODS: Medical records of dogs with AKI treated by hemodialysis between 2011 and 2015 were reviewed. Dogs were included only if all variables required to calculate the final predictive score were available, and the 30-day outcome was known. A predictive score for 3 models was calculated for each dog. Logistic regression was used to evaluate the association of the final predictive score with each model's outcome. Receiver operating curve (ROC) analyses were performed to determine sensitivity and specificity for each model based on previously established cut-off values. RESULTS: Higher scores for each model were associated with decreased survival probability (P < .001). Based on previously established cut-off values, 3 models (models A, B, C) were associated with sensitivities/specificities of 73/75%, 71/80%, and 75/86%, respectively, and correctly classified 74-80% of the dogs. CONCLUSIONS AND CLINICAL RELEVANCE: All models were simple to apply and allowed outcome prediction that closely corresponded with actual outcome in an independent cohort. As expected, accuracies were slightly lower compared with those from the previously reported cohort used initially to develop the models.

Iron Status of Cats with Chronic Kidney Disease.

BACKGROUND: Iron deficiency is a proposed mechanism for the anemia that occurs in cats with chronic kidney disease (CKD). Minimal research investigating the iron status of these cats has been performed. OBJECTIVE: To compare indicators of iron status in cats with CKD versus healthy cats and cats with nonrenal illness (NRI). To compare indicators of iron status in anemic versus nonanemic cats with CKD. ANIMALS: Thiry-nine client or employee owned healthy cats, 40 cats with CKD and 34 cats with NRI included. METHODS: Exclusion criteria included prior iron or erythropoiesis stimulating agent administration, blood transfusion, or concurrent CKD and NRI. Complete blood counts, serum chemistries, serum iron concentrations, total iron binding capacity (TIBC), and ferritin concentrations were measured and percent transferrin saturation (TSAT) calculated on all cats. Data were analyzed using nonparametric statistical testing. RESULTS: No statistically significant differences were detected among groups for iron concentration (P = .50), ferritin concentration (P = .47), or TSAT (P = .19). TIBC was significantly lower in CKD (median 262 µg/dL; IQR 233-302; range 165-488) versus healthy cats (median 316 µg/dL; IQR 272-345, range 196-464); (P = .0030). When comparing anemic (hemoglobin <9.5 g/dL) versus nonanemic cats with CKD, TSAT was significantly lower (P = .033) in anemic (median 20.2%; IQR 17.8-34.5; range 17.6-35.9) compared to nonanemic (median 29.0%; IQR 25.5-44.1; range 11.5-94.4). No statistically significant differences found for ferritin concentration (P = .94), iron concentration (P = .21) or TIBC (P = .97). CONCLUSIONS AND CLINICAL IMPORTANCE: These results indicate that an iron deficient state exists in anemic cats with CKD and is more likely functional rather than absolute.

Use of tissue plasminogen activator in catheters used for extracorporeal renal replacement therapy.

BACKGROUND: Intraluminal thrombosis of central venous catheters used for renal replacement therapy (RRT) decreases the ability to provide adequate treatment. Alteplase is a recombinant tissue plasminogen activator that has been used to improve the function of catheters used for RRT in humans. OBJECTIVES: To retrospectively review alteplase instillation in dysfunctional catheters used for RRT in dogs and cats. ANIMALS: Seventeen dogs and 8 cats receiving RRT for kidney failure. METHODS: Medical records of patients in which alteplase was used for RRT catheter dysfunction from 2004 to 2012 were retrospectively reviewed to characterize reasons for use, improvement in function, increase in blood flow, and duration of improvement. RESULTS: Alteplase was instilled 43 times in 29 catheters, most commonly because of suspicion that the catheter would not provide sufficient flow on the next treatment (n = 21). The second most common reason was inability to start a dialysis treatment (n = 12). Catheter function improved after alteplase instillation in 34 of 43 treatments (79%). Median blood flow rate increased by 13% (18 mL/min) in the dialysis session after alteplase instillation. Seven of 29 catheters (24%) were treated with alteplase on >1 occasion (median time to second treatment, 8 days), and 1 catheter had to be replaced because of intractable dysfunction. CONCLUSIONS AND CLINICAL IMPORTANCE: Alteplase is effective at improving function of central venous catheters used to provide RRT, but the results are short-lived.

Robust T cell responses to aspergillosis in chronic granulomatous disease: implications for immunotherapy.

Chronic granulomatous disease (CGD) patients are highly susceptible to invasive aspergillosis and might benefit from aspergillus-specific T cell immunotherapy, which has shown promise in treating those with known T cell defects such as haematopoietic stem cell transplant (HSCT) recipients. But whether such T cell defects contribute to increased risks for aspergillus infection in CGD is unclear. Hence, we set out to characterize the aspergillus-specific T cell response in CGD. In murine CGD models and in patients with CGD we showed that the CD4(+) T cell responses to aspergillus were unimpaired: aspergillus-specific T cell frequencies were even elevated in CGD mice (P < 0·01) and humans (P = 0·02), compared to their healthy counterparts. CD4-depleted murine models suggested that the role of T cells might be redundant because resistance to aspergillus infection was conserved in CD4(+) T cell-depleted mice, similar to wild-type animals. In contrast, mice depleted of neutrophils alone or neutrophils and CD4(+) T cells developed clinical and pathological evidence of pulmonary aspergillosis and increased mortality (P < 0·05 compared to non-depleted animals). Our findings that T cells in CGD have a robust aspergillus CD4(+) T cell response suggest that CD4(+) T cell-based immunotherapy for this disease is unlikely to be beneficial.

Multidose pharmacokinetics of orally administered florfenicol in the channel catfish (Ictalurus punctatus).

Plasma disposition of florfenicol in channel catfish was investigated after an oral multidose (10 mg/kg for 10 days) administration in freshwater at water temperatures ranging from 24.7 to 25.9 °C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography with MS/MS detection. After the administration of florfenicol, the mean terminal half-life (t(1/2)), maximum concentration at steady-state (Css (max)), time of Css (max) (T(max)), minimal concentration at steady-state (Css (min)), and Vc /F were 9.0 h, 9.72 µg/mL, 8 h, 2.53 µg/mL, and 0.653 L/kg, respectively. These results suggest that florfenicol administered orally at 10 mg/kg body weight for 10 days could be expected to control catfish bacterial pathogens inhibited in vitro by a minimal inhibitory concentration value of <2.5 µg/mL.

Consensus guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis.

BACKGROUND: In certain situations, veterinarians must decide whether or not to recommend immunosuppressive therapy for dogs with suspect glomerular disease in the absence of renal biopsy-derived evidence that active immune mechanisms are contributing to glomerular injury. The purpose of this report is to provide guidelines for the use of immunosuppressive drugs under these conditions. ANIMALS: Animals were not used in this study. METHODS: Recommendations were developed by a formal consensus method. RESULTS: Four recommendations were developed and accepted at a high level of consensus (median 92.5% agreement). Renal biopsy should not be performed when contraindications are present or when results will not alter treatment or outcome. Immunosuppressive drugs should not be given when the source of proteinuria is unknown, they are otherwise contraindicated, or a familial nephropathy or amyloidosis is likely. However, they should be considered when dogs are already being given standard therapy and the serum creatinine is >3.0 mg/dL, azotemia is progressive, or hypoalbuminemia is severe. Thorough client communication regarding pros and cons of such treatment as well as close and careful patient monitoring is required. CONCLUSION AND CLINICAL IMPORTANCE: These recommendations can help guide the decision about renal biopsy in patients with proteinuria as well as the use of immunosuppressive drugs in those patients where the decision was made not to perform renal biopsy.

The effects of cyclosporine on platelet function and cyclooxygenase expression in normal dogs.

BACKGROUND: Cyclosporine has been shown to alter platelet plasma membranes and have a hypercoagulable effect in humans, leading to thromboembolic complications. HYPOTHESIS/OBJECTIVES: Our hypothesis was that by modulating platelet reactivity, cyclosporine increases the risk of thromboembolic complications. The objective was to determine the effects of cyclosporine on primary hemostasis in normal dogs. ANIMALS: Eight healthy, intact female dogs. METHODS: A repeated-measures design utilized flow cytometry to evaluate platelet expression of platelet reactivity markers (P-selectin and phosphatidylserine) and COX-1 and COX-2 during the administration of 2 cyclosporine dosages (19 mg/kg q12h [immunosuppressive dosage] and 5 mg/kg q24h [atopy dosage]). Urine 11-dehydro-thromboxane-B(2) (11-dTXB(2) ) concentration was normalized to urine creatinine concentration, and platelet function was analyzed by PFA-100. RESULTS: After a week of the immunosuppressive dosage, all platelet reactivity markers showed a significant decrease in mean fluorescent intensity (MFI). After the atopy dosage, only P-selectin and COX-2 MFI demonstrated a change from baseline, decreasing by 29% (P = .013) and 31% (P = .003), respectively. Urinary 11-dTXB(2) -to-creatinine ratio significantly increased at all time points during the immunosuppressive dosage, but no significant change occurred during administration of the atopy dosage. PFA-100 closure times using collagen/ADP cartridges increased by 62% (P = .008) with the immunosuppressive dosage and decreased by 45% with the atopy dosage (P = .035). No significant changes in closure times occurred with collagen/epinephrine cartridges. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that, similar to what is observed in humans, cyclosporine alters the platelet plasma membrane and increases thromboxane production in dogs, especially at immunosuppressive dosages.

Acute azotemia as a predictor of mortality in dogs and cats.

BACKGROUND: Acute kidney injury (AKI) has been shown to be a predictor of mortality in human medicine. Published studies in the veterinary literature evaluating relative changes in serum creatinine concentration as a prognostic factor are limited. OBJECTIVE: To evaluate an AKI grading system based on serum creatinine concentration to determine if it correlates with outcome prediction in dogs and cats. ANIMALS: Six hundred forty-five dogs and 209 cats that had at least 2 serum creatinine concentration measurements measured within 7 days. METHODS: Retrospective study. Dogs and cats with an initial serum creatinine concentrations of ≤ 1.6 mg/dL and that had more than 1 concentration measured within 2, 3, and 7 days were placed into levels (0-2) based on absolute changes. Mortality then was determined at 30 and 90 days. RESULTS: Based on odds ratios calculated with a 95% confidence interval, dogs placed in level 1 within 2 days were approximately 3 times more likely to die within 90 days. Dogs placed in level 2 within 2, 3, or 7 days were approximately 3 times more likely to die within 30 or 90 days. Cats placed in level 2 within 3 or 7 days were approximately 3 times more likely to die at 30 days and 4 times more likely to die if placed in this level within 7 days. If placed in level 2 within 2 or 3 days, cats were approximately 3 times more likely to die within 90 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Detecting increasing severity of azotemia helps predict mortality in dogs and cats.

The use of darbepoetin to stimulate erythropoiesis in anemia of chronic kidney disease in cats: 25 cases.

BACKGROUND: Anemia is present in 30-65% in cats with chronic kidney disease (CKD) and few long-term treatment options exist. Darbepoetin is effective in treating anemia of kidney disease in humans and may be used in cats. HYPOTHESIS/OBJECTIVE: To evaluate the use of darbepoetin, a recombinant analog of human erythropoietin, to stimulate erythropoiesis, and to effectively treat anemia of kidney disease in cats. ANIMALS: Twenty-five of 66 cats that received ≥ 2 doses of darbepoetin at the Animal Medical Center between January 2005 and December 2009 were included in this study. METHODS: Cats were included in the study if they received darbepoetin and follow-up data were available for at least 56 days and had CKD as a primary clinical diagnosis. Cats were excluded if they were treated with darbepoetin but did not have kidney disease. Response to treatment was defined as reaching or exceeding a target packed red blood cell volume or hematocrit of 25%. RESULTS: Fourteen of 25 cats responded. Thirteen of those 14 cats received a dosage of 1 µg/kg/wk or higher. Presumptive adverse effects included vomiting, hypertension, seizures, and fever. CONCLUSIONS AND CLINICAL RELEVANCE: Darbepoetin is effective for treatment of anemia of kidney disease in cats. Pure red cell aplasia appears to be less common with darbepoetin than with epoetin usage.

Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish (Ictalurus punctatus).

Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10 mg/kg) of intravenous (i.v.) or oral administration in freshwater at a mean water temperature of 25.4 °C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography with MS/MS detection. After i.v. florfenicol injection, the terminal half-life (t(1/2)), volume of distribution at steady state (V(ss)), and central volume of distribution (V(c)) were 8.25 h, 0.9 and 0.381 L/kg, respectively. After oral administration of florfenicol, the terminal t(1/2), C(max), T(max), and oral bioavailability (F) were 9.11 h, 7.6 µg/mL, 9.2 h, and 1.09, respectively. There was a lag absorption time of 1.67 h in oral dosing. Results from these studies support that 10 mg florfenicol/kg body weight in channel catfish is an efficacious dosage following oral administration.

Platelet cyclooxygenase expression in normal dogs.

BACKGROUND: Human platelets express both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Variation in COX-2 expression could be a mechanism for variable response to aspirin. HYPOTHESIS/OBJECTIVES: The hypotheses were that circulating canine platelets express COX-1 and COX-2, and that aspirin alters COX expression. The objective was to identify changes in platelet COX expression and in platelet function caused by aspirin administration to dogs. ANIMALS: Eight female, intact hounds. METHODS: A single population, repeated measures design was used to evaluate platelet COX-1 and COX-2 expression by flow cytometry before and after aspirin (10 mg/kg Q12h for 10 days). Platelet function was analyzed via PFA-100(®) (collagen/epinephrine), and urine 11-dehydro-thromboxane B(2) (11-dTXB(2)) was measured and normalized to urinary creatinine. Differences in COX expression, PFA-100(®) closure times, and urine 11-dTXB(2 ): creatinine ratio were analyzed before and after aspirin administration. RESULTS: Both COX-1 and COX-2 were expressed in canine platelets. COX-1 mean fluorescent intensity (MFI) increased in all dogs, by 250% (range 63-476%), while COX-2 expression did not change significantly (P = 0.124) after aspirin exposure, with large interindividual variation. PFA-100(®) closure times were prolonged and urine 11-dTXB(2) concentration decreased in all dogs after aspirin administration. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine platelets express both COX isoforms. After aspirin exposure, COX-1 expression increased despite impairment of platelet function, while COX-2 expression varied markedly among dogs. Variability in platelet COX-2 expression should be explored as a potential mechanism for, or marker of, variable aspirin responsiveness.

Evaluation of in vitro serial antibiotic elution from meropenem-impregnated polymethylmethacrylate beads after ethylene oxide gas and autoclave sterilization.

OBJECTIVES: To determine the elution properties of meropenem and to compare the elutions of meropenem-impregnated polymethylmethacrylate (PMMA) beads without sterilization (P-M-C) to those sterilized with steam (P-M-A) and ethylene oxide gas (P-M-EO). METHODS: A commercial bead mould was used to produce four groups of beads: one group without antibiotic (negative control), and three groups of meropenem-impregnated beads: P-M-C, P-M-A, and P-M-EO. The beads were placed in a phosphate buffered solution and eluent samples were collected. Concentrations of the antibiotic in eluent samples from the two sterilized groups and the control beads were determined using a microbiological assay at 1, 3, 6 and 12 hours and at 1, 2, 3, 6, 9, 12, 15, 18, 22, 26, and 30 days. RESULTS: The microbiological assay resulted in no zone of inhibition at all time periods for the P-M-A samples and the samples of PMMA without antimicrobial. The meropenem concentration on the eluent remained above 4 mcg/ml for 15 days in the P-M-C group and until day 18 for P-M-EO group. There was no statistical difference in AUC0-∞ (p<0.318), however significance did occur for MRT (p<0.005) when comparing P-M-C and P-M-EO with the later being higher. DISCUSSION: The meropenem incorporated in the PMMA beads eluted effectively and gradually decreased after the 24 hour peak, but remained above the concentration level of 4 mcg/ml for 15 days in the P-M-C group and until day 18 for P-M-EO group. Ethylene oxide does not adversely affect meropenem's elution from PMMA beads.

Familial neuroendocrine cell hyperplasia of infancy.

BACKGROUND: Neuroendocrine cell hyperplasia of infancy (NEHI) is a recently described children's interstitial lung disease (chILD) disorder of unknown etiology. It manifests clinically with tachypnea, retractions, hypoxemia, and crackles. The characteristic radiographic appearance consists of pulmonary hyperexpansion and ground-glass densities on high-resolution computed tomography (HRCT). Lung histology shows hyperplasia of bombesin-immunopositive neuroendocrine cells within distal bronchioles and alveolar ducts without other identifiable lung pathology or developmental anomaly. METHODS: We describe four families with multiple siblings diagnosed with NEHI. Cases were identified at three pediatric centers. Inclusion criteria included clinical findings consistent with NEHI, lung biopsy confirmation in the index case, and a diagnostic HRCT or biopsy in other siblings. RESULTS: Each family had a proband diagnosed with NEHI based upon pathologic review, and at least one additional sibling diagnosed either by pathologic review or HRCT. All patients presented between 2 and 15 months of age. Both male and female children were affected. The majority of the patients underwent both HRCT and lung biopsy. There were no deaths among affected children. No environmental exposures or other potential etiologies were identified as a cause of presenting symptoms. CONCLUSIONS: The familial occurrence of NEHI suggests the possibility of a genetic etiology for this disorder and highlights the importance of taking a complete family medical history for infants presenting with a suggestive clinical picture. Identification of familial NEHI patients allows for the opportunity to further our understanding of this disorder, its natural history, the phenotypic spectrum, and potential genetic causes.

Survival in cats with naturally occurring chronic kidney disease (2000-2002).

BACKGROUND: Duration of survival of cats with naturally occurring chronic kidney disease (CKD) is poorly characterized. HYPOTHESIS: Stage of kidney disease based on serum creatinine concentration (SCr) at the time of diagnosis and after correction of prerenal azotemia is strongly associated with duration of survival in cats. ANIMALS: Two hundred and eleven client-owned cats with naturally occurring CKD evaluated between April 2000 and January 2002. METHODS: Retrospective case review of 733 cats with SCr > 2.3 mg/dL. Examination of the medical records identified 211 cats that met all other inclusion and exclusion criteria for this study. Clinical characteristics, clinicopathologic data, and survival times were extracted from the medical record. Owners and referring veterinarians were contacted by phone to obtain follow-up if it was not documented in the record. Kaplan-Meier survival curves were performed to determine survival times for International Renal Interest Society (IRIS) stage both at diagnosis and at baseline (ie, after correction of prerenal azotemia). RESULTS: Median survival for cats in IRIS stage IIb at the time of diagnosis was 1,151 days (range 2-3,107), and was longer than survival in stage III (median 778, range 22-2,100) or stage IV (median 103, range 1-1,920) (P-value< .0001). P-value for effect of stage at diagnosis was < .0001. CONCLUSIONS AND CLINICAL IMPORTANCE: IRIS stage of CKD based on serum creatinine at the time of diagnosis is strongly predictive of survival in cats with naturally occurring CKD.

Clinical, radiological and pathological features of ABCA3 mutations in children.

BACKGROUND: Mutations in the ABCA3 gene can result in fatal surfactant deficiency in term newborn infants and chronic interstitial lung disease in older children. Previous studies on ABCA3 mutations have focused primarily on the genetic abnormalities and reported limited clinical information about the resultant disease. A study was undertaken to analyse systematically the clinical presentation, pulmonary function, diagnostic imaging, pathological features and outcomes of children with ABCA3 mutations. METHODS: The records of nine children with ABCA3 mutations evaluated at Texas Children's Hospital between 1992 and 2005 were reviewed and their current clinical status updated. Previous diagnostic imaging studies and lung biopsy specimens were re-examined. The results of DNA analyses were confirmed. RESULTS: Age at symptom onset ranged from birth to 4 years. Cough, crackles, failure to thrive and clubbing were frequent findings. Mean lung function was low but tended to remain static. CT scans commonly revealed ground-glass opacification, septal thickening, parenchymal cysts and pectus excavatum. Histopathological patterns included pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis, and varied with age. Dense abnormalities of lamellar bodies, characteristic of ABCA3 mutations, were seen by electron microscopy in all adequate specimens. Outcomes varied with the age at which the severity of lung disease warranted open lung biopsy, and some patients have had prolonged survival without lung transplantation. CONCLUSIONS: The presentation and course of interstitial lung disease due to ABCA3 mutations are variable, and open lung biopsy and genetic testing are warranted early in the evaluation of children with a consistent clinical picture.