Episodes Of Pneumonia Research Articles

A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare.Case presentationWe herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES).ConclusionsAlthough rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

Diagnosis of Early Bacterial Pneumonia and Sepsis After Cardiovascular Surgery: A Diagnostic Prediction Model Based on LASSO Logistic Regression.

Early postoperative bacterial pneumonia and sepsis (ePOPS), which occurs within the first 48 hours after cardiovascular surgery, is a serious life-threatening complication. Diagnosis of ePOPS is extremely challenging, and the existing diagnostic tools are insufficient. The purpose of this study was to construct a novel diagnostic prediction model for ePOPS. Least Absolute Shrinkage and Selection Operator (LASSO) with logistic regression was used to construct a model to diagnose ePOPS based on patients' comorbidities, medical history, and laboratory findings.The area under the receiver operating characteristic curve (AUC) was used to evaluate the model discrimination. A total of 1203 patients were recruited and randomly split into a training and validation set in a 7:3 ratio. By early morning on the 3rd postoperative day (POD3), 103 patients had experienced 133 episodes of bacterial pneumonia or sepsis (15 patients had both). LASSO logistic regression model showed that duration of mechanical ventilation (P=0.015), NYHA class ≥ III (P=0.001), diabetes (P<0.001), exudation on chest radiograph (P=0.011) and IL-6 on POD3 (P<0.001) were independent risk factors. Based on these factors, we created a nomogram named DICS-I with an AUC of 0.787 in the training set and 0.739 in the validation set. The DICS-I model may be used to predict the risk of ePOPS after cardiovascular surgery, and is also especially suitable for predicting the risk of IRAO. The DICS-I model could help clinicians to adjust antibiotics on the POD3.

Low and high serum IgG associates with respiratory infections in a young and working age population.

We investigated health consequences and genetic properties associated with serum IgG concentration in a young and working age general population. Northern Finland Birth Cohort 1966 (NFBC1966, n=12,231) health data have been collected from birth to 52 years of age. Relationships between life-long health events, medications, chronic conditions, lifestyle, and serum IgG concentration measured at age 46 years (n=5430) were analysed. Regulatory mechanisms of serum IgG concentration were considered. Smoking and genetic variation (FCGR2B and TNFRSF13B) were the most important determinants of serum IgG concentration. Laboratory findings suggestive of common variable immunodeficiency (CVID) were 10-fold higher compared to previous reports (73.7 per 100,000 vs 0.6-6.9 per 100,000). Low IgG was associated with antibiotic use (relative risk 1.285, 95% CI 1.001-1.648; p=0.049) and sinus surgery (relative risk 2.257, 95% CI 1.163-4.379; p=0.016). High serum IgG was associated with at least one pneumonia episode (relative risk 1.737, 95% CI 1.032-2.922; p=0.038) and with total number of pneumonia episodes (relative risk 2.167, 95% CI 1.443-3.254; p<0.001). CVID-like laboratory findings are surprisingly common in our unselected study population. Any deviation of serum IgG from normal values can be harmful; both low and high serum IgG may indicate immunological insufficiency. Critical evaluation of clinical presentation must accompany immunological laboratory parameters. Oulu University Hospital VTR, CSL Behring, Foundation for Pediatric Research.

Short-course antibiotic therapy for pneumonia in the neonatal intensive care unit.

To determine the adherence and safety outcomes of a 5-day antibiotic course with a "time-out" for treatment of "blood culture-negative" pneumonia in the NICU. Prospective surveillance of all infants diagnosed with pneumonia at 7 NICUs from 8/2020-12/2021. Safety outcomes were defined a priori by re-initiation of antibiotic therapy within 14 days after discontinuation and overall and sepsis-related mortality. 128 infants were diagnosed with 136 episodes of pneumonia; 88% (n = 119) were treated with 5 days of definitive antibiotic therapy. Antibiotics were restarted within 14 days in 22 (16%) of the 136 pneumonia episodes. However, only 3 (3%) of the 119 episodes of pneumonia treated for 5 days had antibiotics restarted for pneumonia. Mortality was 5% (7/128); 5 of the 7 deaths were assessed as sepsis-related. Adherence to the 5-day definitive antibiotic treatment for "culture-negative" pneumonia was high and the intervention seemed safe.

Fiberoptic Endoscopic Evaluation of Swallowing Findings in Children With Rett Syndrome.

Feeding abnormalities, swallowing dysfunction, and gastrointestinal issues cause poor weight gain, oral motor dysfunction, and air swallowing in children with Rett syndrome (RTT). Pneumonia is the leading cause of death. Our study describes fiberoptic endoscopic swallowing findings in 11 female RTT children. Each patient was evaluated using the 8-point Penetration/Aspiration Scale (PAS). The average age was 7 years. All patients had tongue dyskinesis and prolonged oral stage. Eight girls exhibited liquid entering the airway without coughing, whereas 6 did well with pureed meal. Three girls had pneumonia. Age was not correlated with pneumonia episodes (P = .18). Pureed material was related with pneumonia (P = .006), whereas liquids were not. Pureed PAS was positively correlated with Liquid PAS (P = .008) and age (P = .004). All aspiration/penetration incidents occurred before the pharyngeal phase. No patient under 7 years experienced pneumonia episodes. Silent aspiration can occur early in infancy, although pneumonia episodes can occur later.

An Adjudication Protocol for Severe Pneumonia.

Clinical end points that constitute successful treatment in severe pneumonia are difficult to ascertain and vulnerable to bias. The utility of a protocolized adjudication procedure to determine meaningful end points in severe pneumonia has not been well described. This was a single-center prospective cohort study of patients with severe pneumonia admitted to the medical intensive care unit. The objective was to develop an adjudication protocol for severe bacterial and/or viral pneumonia. Each episode of pneumonia was independently reviewed by 2 pulmonary and critical care physicians. If a discrepancy occurred between the 2 adjudicators, a third adjudicator reviewed the case. If a discrepancy remained after all 3 adjudications, consensus was achieved through committee review. Evaluation of 784 pneumonia episodes during 593 hospitalizations achieved only 48.1% interobserver agreement between the first 2 adjudicators and 78.8% when agreement was defined as concordance between 2 of 3 adjudicators. Multiple episodes of pneumonia and presence of bacterial/viral coinfection in the initial pneumonia episode were associated with lower interobserver agreement. For an initial episode of bacterial pneumonia, patients with an adjudicated day 7-8 clinical impression of cure (compared with alternative impressions) were more likely to be discharged alive (odds ratio, 6.3; 95% CI, 3.5-11.6). A comprehensive adjudication protocol to identify clinical end points in severe pneumonia resulted in only moderate interobserver agreement. An adjudicated end point of clinical cure by day 7-8 was associated with more favorable hospital discharge dispositions, suggesting that clinical cure by day 7-8 may be a valid end point to use in adjudication protocols.

Can You Establish the Cause of This Patient's Shortness of Breath?

Mr. B is a 56-year-old man diagnosed with metastatic HER2-positive gastroesophageal adenocarcinoma. He received front-line leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) and trastuzumab for 10 months before restaging imaging revealed progressive disease. He then received second-line trastuzumab deruxtecan. His treatment was complicated by several admissions felt to be unrelated to his cancer therapy. He was discharged after an episode of pneumonia on a steroid taper with prophylactic trimethoprim/sulfamethoxazole. Once he recovered, he was given a fourth dose of chemotherapy. About a week later, wheezes were noticed on physical exam, and he was given a 5-day course of levofloxacin. Around the same time, he also finished his steroid taper. Twelve days after his dose of chemotherapy, he presented to the emergency room with 3 to 4 days of progressive shortness of breath and dry cough following the completion of levofloxacin without symptom improvement. A CT scan showed increasing airspace opacities and multifocal areas of consolidation. Blood, nasal, and sputum cultures were negative. A bronchoscopy was performed that did not reveal findings concerning for capillaritis. He was ultimately diagnosed with drug-induced pneumonitis/interstitial lung disease (ILD). Mr. B continued to experience worsening hypoxic respiratory failure despite continuous IV steroids. He was discharged to an inpatient hospice facility where he passed away 2 weeks later. Drug-induced pneumonitis/ILD should be considered in all patients receiving trastuzumab deruxtecan who develop progressive shortness of breath or other respiratory complaints.

FINCA syndrome

FINCA (fibrosis, neuro-degeneration, cerebral angiomatosis) syndrome is a rare autosomal recessive early onset fatal disorder characterised by progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infection, chronic haemolytic anaemia and transient liver dysfunction. A 5 year old female baby born as a preterm 33 weeks (2nd twin of dichorionic diamniotic twin) to nonconsanguineous parents via intra-cytoplasmic sperm injection and surrogacy, delivered by emergency caesarean section (indication- pre-eclampsia in mother) with a birth weight of 1.8 kg. She had a stormy neonatal period and had anaemia requiring blood transfusion. Developmental delay was noted from early infancy which was not responding to developmental therapy, along with recurrent episodes of aspiration pneumonia. Her twin on the other hand had normal mile stones without any remarkable medical history. Examination and evaluation revealed features of chronic hemolysis. In view of constellation of developmental delay, recurrent infection, chronic hemolytic anaemia and cerebral atrophy beyond documented perinatal issues and dysmorphism, clinical exome sequencing was done which revealed missense variation in exon of NHLRC2 gene on chromosome 10 suggestive of FINCA syndrome. This case emphasized the need of genetic testing to resolve uncertainty in etiology and accurate prognostication.

Identifying sensitive windows of prenatal household air pollution on birth weight and infant pneumonia risk to inform future interventions

BackgroundPrenatal household air pollution impairs birth weight and increases pneumonia risk however time-varying associations have not been elucidated and may have implications for the timing of public health interventions. MethodsThe Ghana Randomized Air Pollution and Health Study (GRAPHS) enrolled 1,414 pregnant women from Kintampo, Ghana and measured personal carbon monoxide (CO) exposure four times over pregnancy. Birth weight was measured within 72-hours of birth. Fieldworkers performed weekly pneumonia surveillance and referred sick children to study physicians. The primary pneumonia outcome was one or more physician-diagnosed severe pneumonia episode in the first year of life. We employed reverse distributed lag models to examine time-varying associations between prenatal CO exposure and birth weight and infant pneumonia risk. ResultsAnalyses included n = 1,196 mother-infant pairs. In models adjusting for child sex; maternal age, body mass index (BMI), ethnicity and parity at enrollment; household wealth index; number of antenatal visits; and evidence of placental malaria, prenatal CO exposures from 15 to 20 weeks gestation were inversely associated with birth weight. Sex-stratified models identified a similar sensitive window in males and a window at 10-weeks gestation in females. In models adjusting for child sex, maternal age, BMI and ethnicity, household wealth index, gestational age at delivery and average postnatal child CO exposure, CO exposure during 34–39 weeks gestation were positively associated with severe pneumonia risk, especially in females. ConclusionsHousehold air pollution exposures in mid- and late- gestation are associated with lower birth weight and higher pneumonia risk, respectively. These findings support the urgent need for deployment of clean fuel stove interventions beginning in early pregnancy.

Burden, predictors, and outcome of unconsciousness among under-five children hospitalized for community-acquired pneumonia: A retrospective study from a developing country.

Despite the reduction of death from pneumonia over recent years, pneumonia has still been the leading infectious cause of death in under-five children for the last several decades. Unconsciousness is a critical condition in any child resulting from any illness. Once it occurs during a pneumonia episode, the outcome is perceived to be fatal. However, data on children under five with pneumonia having unconsciousness are scarce. We've retrospectively analyzed the data of under-five children admitted at the in-patient ward of Dhaka Hospital of icddr,b during 1 January 2014 and 31 December 2017 with World Health Organization classified pneumonia or severe pneumonia. Children presented with or without unconsciousness were considered as cases and controls respectively. Among a total of 3,876 children fulfilling the inclusion criteria, 325 and 3,551 were the cases and the controls respectively. A multivariable logistic regression analysis revealed older children (8 months vs. 7.9 months) (adjusted odds ratio, aOR 1.02, 95% CI: 1.004-1.04, p = 0.015), hypoxemia (aOR 3.22, 95% CI: 2.39-4.34, p<0.001), severe sepsis (aOR 4.46, 95% CI: 3.28-6.06, p<0.001), convulsion (aOR 8.90, 95% CI: 6.72-11.79, p<0.001), and dehydration (aOR 2.08, 95% CI: 1.56-2.76, p<0.001) were found to be independently associated with the cases. The cases more often had a fatal outcome than the controls (23% vs. 3%, OR 9.56, 95% CI: 6.95-13.19, p<0.001). If the simple predicting factors of unconsciousness in children under five hospitalized for pneumonia with different severity can be initially identified and adequately treated with prompt response, pneumonia-related deaths can be reduced more effectively, especially in resource-limited settings.

Machine learning links unresolving secondary pneumonia to mortality in patients with severe pneumonia, including COVID-19.

BACKGROUNDDespite guidelines promoting the prevention and aggressive treatment of ventilator-associated pneumonia (VAP), the importance of VAP as a driver of outcomes in mechanically ventilated patients, including patients with severe COVID-19, remains unclear. We aimed to determine the contribution of unsuccessful treatment of VAP to mortality for patients with severe pneumonia.METHODSWe performed a single-center, prospective cohort study of 585 mechanically ventilated patients with severe pneumonia and respiratory failure, 190 of whom had COVID-19, who underwent at least 1 bronchoalveolar lavage. A panel of intensive care unit (ICU) physicians adjudicated the pneumonia episodes and endpoints on the basis of clinical and microbiological data. Given the relatively long ICU length of stay (LOS) among patients with COVID-19, we developed a machine-learning approach called CarpeDiem, which grouped similar ICU patient-days into clinical states based on electronic health record data.RESULTSCarpeDiem revealed that the long ICU LOS among patients with COVID-19 was attributable to long stays in clinical states characterized primarily by respiratory failure. While VAP was not associated with mortality overall, the mortality rate was higher for patients with 1 episode of unsuccessfully treated VAP compared with those with successfully treated VAP (76.4% versus 17.6%, P < 0.001). For all patients, including those with COVID-19, CarpeDiem demonstrated that unresolving VAP was associated with a transitions to clinical states associated with higher mortality.CONCLUSIONSUnsuccessful treatment of VAP is associated with higher mortality. The relatively long LOS for patients with COVID-19 was primarily due to prolonged respiratory failure, placing them at higher risk of VAP.FUNDINGNational Institute of Allergy and Infectious Diseases (NIAID), NIH grant U19AI135964; National Heart, Lung, and Blood Institute (NHLBI), NIH grants R01HL147575, R01HL149883, R01HL153122, R01HL153312, R01HL154686, R01HL158139, P01HL071643, and P01HL154998; National Heart, Lung, and Blood Institute (NHLBI), NIH training grants T32HL076139 and F32HL162377; National Institute on Aging (NIA), NIH grants K99AG068544, R21AG075423, and P01AG049665; National Library of Medicine (NLM), NIH grant R01LM013337; National Center for Advancing Translational Sciences (NCATS), NIH grant U01TR003528; Veterans Affairs grant I01CX001777; Chicago Biomedical Consortium grant; Northwestern University Dixon Translational Science Award; Simpson Querrey Lung Institute for Translational Science (SQLIFTS); Canning Thoracic Institute of Northwestern Medicine.

Incidence and clinical outcomes of pneumonia in persons with down syndrome in the United States

BackgroundPersons with Down syndrome (DS) experience an increased risk of pneumonia. We determined the incidence and outcomes of pneumonia and relationship to underlying comorbidities in persons with and without DS in the United States. MethodsThis retrospective matched cohort study used de-identified administrative claims data from Optum. Persons with DS were matched 1:4 to persons without DS on age, sex, and race/ethnicity. Pneumonia episodes were analyzed for incidence, rate ratios and 95 % confidence intervals, clinical outcomes, and comorbidities. ResultsDuring 1-year follow-up among 33796 persons with and 135184 without DS, the incidence of all-cause pneumonia (pneumonia) was substantially higher among people with DS than those without DS (12427 vs. 2531 episodes/100000 person-years; 4.7–5.7 fold increase). Persons with DS and pneumonia were more likely to be hospitalized (39.4 % vs. 13.9 %) or admitted to the ICU (16.8 % vs. 4.8 %). Mortality was higher 1 year after first pneumonia (5.7 % vs. 2.4 %; P < 0.0001). Results were similar for episodes of pneumococcal pneumonia. Specific comorbidities were associated with pneumonia, particularly heart disease in children and neurologic disease in adults, which only partially mediated the effect of DS on pneumonia. ConclusionsAmong persons with DS, incidence of pneumonia and associated hospitalizations were increased; mortality among those with pneumonia was comparable at 30 days, but higher at 1 year. DS should be considered an independent risk condition for pneumonia.

Proton pump inhibitor use and risk of pneumonia: a self-controlled case series study.

Recent research indicates that use of proton pump inhibitors (PPIs) is associated with pneumonia, but existing evidence is inconclusive because of methodological issues. This study aimed to answer whether PPI-use increases risk of pneumonia while taking the methodological concerns of previous research into account. This population-based and nationwide Swedish study conducted in 2005-2019 used a self-controlled case series design. Data came from national registries for medications, diagnoses, and mortality. Conditional fixed-effect Poisson regression provided incidence rate ratios (IRR) with 95% confidence intervals (CI) for pneumonia comparing PPI-exposed periods with unexposed periods in the same individuals, thus controlling for confounding. Analyses were stratified by PPI-treatment duration, sex, age, and smoking-related diseases. Use of histamine type-2 receptor antagonists (used for the same indications as PPIs) and risk of pneumonia was analysed for assessing the validity and specificity of the results for PPI-therapy and pneumonia. Among 519,152 patients with at least one pneumonia episode during the study period, 307,709 periods of PPI-treatment occurred. PPI-use was followed by an overall 73% increased risk of pneumonia (IRR 1.73, 95% CI 1.71-1.75). The IRRs were increased across strata of PPI-treatment duration, sex, age, and smoking-related disease status. No such strong association was found between histamine type-2 receptor antagonist use and risk of pneumonia (IRR 1.08, 95% CI 1.02-1.14). PPI-use seems to be associated with an increased risk of pneumonia. This finding highlights a need for caution in using PPIs in individuals with a history of pneumonia.

Empiric anti-Giardia therapy in non-diarrheal protein-losing enteropathy: A focus on children with monogenic humoral immunodeficiency.

Background and Aim: Chronic giardia infection can lead to non-erosive gastrointestinal disorders, including protein-losing enteropathy (PLE). This report describes non-diarrheal PLE in chronic giardiasis in children with defective humoral immunity. Methods: The retrospective report is related to 2 children known to have a monogenic inborn error of immunity. The first patient is a 13-year-old boy with X-linked agammaglobulinemia (Patient-1), and the second is a 5-year-old boy with NF-kB inducing kinase (NIK) deficiency infection. Frequency, growth status, and serum immunoglobulin-G (IgG) trough and albumin levels were monitored (Patient-2). Results: Patient-1 had more frequency of pneumonia but reported no symptoms of gastrointestinal disease, including alteration of bowel habits, change in stool consistency, nausea, vomiting, fatigue, bloating, and abdominal pain. No clinical oedema on examination. His weight remains static at 19-20 kg for about 1.5 years. Simultaneously, hypoproteinaemia was noted (Figure-1). A trial of increasing IVIG (0.7 - 1 g/kg) and the use of subcutaneous immunoglobulin (0.2 g/kg) did not reverse the biochemical and clinical situation. Hypoproteinaemia workup revealed normal liver and kidney functions, normal cardiac function, and no proteinuria. Interestingly, his upper endoscopy showed mild duodenitis and the presence of giardia lamblia at the luminal surface (Figure-2). Following this, a 2-week course of oral metronidazole (7.5 mg/kg/dose BID) resulted in a restoration of therapeutic serum IgG trough and albumin levels. Additionally, the child's nutritional status improved, and the frequency of respiratory infections dropped. In Patient-2, progressive hypoproteinaemia was noted over nine months. Similarly, no gastrointestinal complaints; however, the family reported foul-smelling semisolid stools with regular consistency. His IgG trough level was 2 g/l, and his albumin level was 20 g/l. Despite maximizing IVIG, he developed two episodes of pneumonia and once otitis media. An empiric oral metronidazole course resulted in the amelioration of symptoms and restoration of proteinemia. Meanwhile, faeces microscopy confirmed the presence of Giardia lamblia. Conclusions: Progressive hypoproteinaemia in children with humoral immunodeficiency is a clinical concern. Routine stool microscopy can identify giardia infection despite the ambiguity of gastrointestinal symptoms in such patients. However, a trial of empiric metronidazole therapy should be considered.

758 Correlation between initial and diagnostic bronchoalveolar lavage isolates among patients with inhalation injury and pneumonia

Abstract Introduction Inhalation injury is associated with increased risk of pneumonia. Bronchoscopy with bronchoalveolar lavage (BAL) is commonly used to diagnose and grade inhalation injury while obtaining a microbiological sample. It has been shown that a quarter of patients with inhalation injury have a single bacteria isolated from initial BAL within 12-48 hours of injury. The clinical significance of this and role of antibiotics in this setting are unknown. We investigated the incidence that bacteria isolated during a pneumonia episode were previously isolated on surveillance BAL among patients with inhalation injury. Methods Among patients with inhalation injury admitted to a large ABA-verified burn center from 2009-2022, microbiological isolates from initial BAL and subsequent culture obtained during a pneumonia episode (BAL, sputum), were extracted from medical records. Abbreviated injury severity score (AIS) was used to grade inhalation injury. Hospital-acquired pneumonia (HAP) was defined using CDC PNU1 criteria, and ventilator-associated pneumonia (VAP) was defined using PNU2 criteria with BAL cutoff &amp;gt;10,000 colony forming units (CFU). Results Two-hundred forty-eight patients with inhalation injury who underwent bronchoscopy for airway inspection and surveillance BAL within 48 hours of injury were included in the analysis. Of the 111 who had a bacterial isolate from initial BAL, 23 (21%) subsequently developed HAP or VAP during the hospitalization. Median (IQR) days between bronchoscopy and pneumonia diagnosis was six (2-8.5). In three of the 11 VAP cases (27%), the organisms identified at pneumonia diagnosis matched the organisms identified on initial BAL. Antibiotic use on admission was not associated with re-culture of initial BAL organism during a subsequent pneumonia episode (p=0.071). Conclusions Among patients with inhalation injury and bacteria isolated on surveillance BAL, 21% developed pneumonia during their hospital stay, usually with different bacteria than those isolated at initial bronchoscopy. There was no association between empiric antibiotic use and incidence of initial BAL organisms re-cultured during subsequent pneumonia episode. Applicability of Research to Practice Findings suggest initial BAL isolates cannot guide empiric coverage of pneumonia for patients with inhalation injury. This remains an important area of future research.

Caspase-8 deficiency-a rare cause of immune dysregulation – First case report from India

A 3½-year-old boy presented with generalized lymphadenopathy since 1 year of age. After 5 months of age, he had multiple infections and two episodes of pneumonia. At 2½ years, he developed chronic diarrhea. Colonoscopy showed ileal ulcers and inflammatory pan colitis with skip areas and histopathologic examination showed mild chronic ileitis, villous shortening, and diffused active colitis. Next-generation sequencing revealed a previously reported homozygous missense mutation Caspase-8. Unlike autoimmune lymphoproliferative syndrome, Caspase-8 deficiency states have immunodeficiency, autoimmunity, and early-onset inflammatory bowel disease in addition to lymphoproliferation. Early diagnosis aided by molecular confirmation is essential as haploidentical hematopoietic stem cell transplant is curative.

An Unexpected Diagnosis of MAGT1 Deficiency in a Patient with CVID-like Features, Molluscum Contagiosum and Atopy

Case DescriptionA 6-year-old boy presented to the immunology clinic with recurrent infections. He started to have recurrent otitis media at the age of 18 months. He also had multiple sinus infections and 3–4 episodes of pneumonia. Immunologic evaluation revealed an IgG of 498 (ref 608–1229 mg/dL), an IgA of 20.8 (ref 33–200 mg/dL) and an impaired response to the Streptococcus pneumoniae vaccine. T and B lymphocyte counts were normal. He was started on subcutaneous immunoglobulin replacement therapy after which his IgG level normalized and his frequency of sinopulmonary infections improved. He also has a history of eczema, chronic cough and environmental allergies for which he receives allergen-specific subcutaneous immunotherapy in addition to treatment with an inhaled corticosteroid and omalizumab. The patient also had persistent skin warts on his hands and extensive molluscum contagiosum lesions. He underwent targeted genetic testing for a primary immunodeficiency which revealed a hemizygous pathogenic variant in the magnesium transporter 1 (MAGT1) gene (c.580dup; p.Ser194Phefs*3). This variant is a duplication at nucleotide position 580 that creates a premature stop codon 3 amino acids downstream from this location. The patient subsequently underwent a carbohydrate deficient transferrin test (CDT) for congenital disorders of glycosylation (CDG) that revealed moderately elevated transferrin mono-oligosaccharide to di-oligosaccharide and Apo CIII-1/Apo CIII-2 ratios, consistent with the diagnosis of MAGT1-CDG (XMEN; X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia). Additionally, NKG2D surface expression was reduced by ~90% on the CD8T cells, and by ~85% on the NK cells in the patient sample compared to the control sample assessed in parallel. The patient continues to test negative for EBV infection by PCR. ConclusionXMEN disease (OMIM number 300853) is a rare, combined immunodeficiency resulting from a mutation in the magnesium transporter 1 gene (MAGT1) located on the X chromosome. Only 36 patients have been reported to have this disease thus far. While the clinical phenotype is variable, the disease is often associated with EBV infection. This case is unique in that the patient was diagnosed due to a history of severe warts, atopy, and hypogammaglobulinemia in the absence of EBV infection.

Chronic Rhinosinusitis with Nasal Polyposis in an Adult with Homozygous Variants of Uncertain Significance in ABCA3 Gene

IntroductionThe role of surfactant proteins in pulmonary diseases has been studied extensively. However, little is known about its contribution in diseases involving the nasal mucosa. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease characterized by persistent inflammation of the nasal passage and paranasal sinuses. We present a case of CRSwNP and interstitial lung disease (ILD) with variants of uncertain significance (VUS) in adenosine triphosphate binding cassette subfamily A member 3 (ABCA3) identified as potential genetic etiology. Case DescriptionPatient was a 42-year-old female with chronic obstructive pulmonary disease (COPD) with oxygen-dependance, bronchiectasis, history of hospitalization for bronchiolitis obliterans organizing pneumonia (BOOP) in infancy, who presented for evaluation of CRSwNP and anosmia. Nasal polyps were first discovered around three years of age, requiring more than 25 nasal polypectomies in her lifetime. Evaluation for cystic fibrosis during childhood was unremarkable. She reported only one episode of wheezing and denied aspirin sensitivity. Despite her significant history of BOOP in infancy, the patient remained without pulmonary infections until four years prior to presentation. Since then, she had two episodes of pneumonia and was diagnosed with COPD, leading to chronic oxygen use. Recent spirometry showed severe airflow obstruction, hyperinflation and decreased diffusing capacity for carbon monoxide. Chest CT revealed diffuse bronchiectasis, mucous plugging, and mild ground glass opacity. Patient had negative sweat test and normal alpha-1 antitrypsin level. Genetic testing with Invitae PCD panel and Neonatal Respiratory Distress panel revealed homozygous VUS [c.155C>T (p. Pro52Leu)] in ABCA3 gene. ConclusionOur patient had an atypical course of ILD, remaining asymptomatic most of her life, and CRSwNP. ABCA3 variants are associated with autosomal recessive pulmonary diseases, such as pulmonary surfactant metabolism dysfunction, pediatric ILD and pulmonary fibrosis1. Surfactant phospholipids are known to lower the surface tension in the alveoli, but they also decrease mucus viscosity and help to eliminate inhaled pathogens2,3,4. The pathophysiology of CRSwNP is unclear and the clinical phenotype of the disease varies widely. While the pathogenicity of the variant is not defined, this case raises a possibility that patient’s ABCA3 genotype may contribute to CRSwNP with recalcitrant nasal polyps.

Humoral Immunodeficiency in two patients with Alagille Syndrome

IntroductionAlagille syndrome is an autosomal dominant entity caused by mutations that affect the Notch-Jagged1 signaling pathway. It is characterized by cholestasis due to poor bile ducts, congenital heart disease, skeletal abnormalities, ocular abnormalities and characteristic facial phenotype. We present 2 patients diagnosed with Alagille syndrome who presented associated immunodeficiency and required gammaglobulin treatment. Case 117-year-old male patient, who was liver transplanted at 19 months of the age. At 6 years of life, he underwent splenectomy secondary to immune thrombocytopenic purpura. He presented recurrent otitis and severe, large styes on the eyelids. He developed a first episode of pneumonia at 6. He received double kidney transplantation due to end-stage chronic kidney disease at 9. At the age of 10 laboratory results showed: IgG: 374 mg/dl IgM: 43 mg/dl IgE: 3 UI and IgA: 202 mg/dl. Functional responses against protein and polysaccharide antigens were absent. Lymphocytes populations were normal. He started treatment with intravenous gammaglobulin at 10 years of age. Case 27-year-old male patient with liver involvement, portal hypertension and portal vein cavernomas that evolved to hypersplenism with esophageal and gastric varices and gastrointestinal bleeding that required a splenorenal anastomosis and a stent. He presented a ventricular communication with a severe hypoplasia of the left pulmonary branch. He presented multiple infectious events including pneumococcal pneumonia. Laboratory showed pancytopenia secondary to hypersplenism, CD4 T lymphopenia (<250/uL)) with preserved CD4/CD8 ratio with normal lymphocyte proliferations, IgG: 450 mg/dl, IgM: 21 mg/dl, IgA: 136 mg/dl. A humoral response decay against global Pneumococcal capsular polysaccharide was observed. Variable response to protein antigen was present. Daily chemoprophylaxis with trimethoprim sulfamethoxazole was indicated but he repeated infectious episodes, then subcutaneous gammaglobulin was started. ConclusionsWe present2 patients diagnosed with Alagille syndromewith associated immunodeficiency. The NOTCH/Jagged 1 signaling pathway is of profound relevance to the process of somitogenesis and in the development of CD4 and CD8 lymphocytes. The immune compromise of patients with Alagille syndrome should be emphasized and eventually gammaglobulin treatment should be indicated.

Case of a 38-year-old man with NEMO deficiency syndrome complicated by marginal zone lymphoma

Here, we present a unique case of a 38-year-old man with history of Nuclear Factor-Kappa B Essential Modulator (NEMO) deficiency syndrome, whose course was complicated by marginal zone lymphoma. At 7 years of age, he was found to have MAI infection and throughout his life, developed further complications of MAI including osteomyelitis, intracranial lesions, adrenal abscesses, and cavitary pulmonary disease. Genetic testing revealed 1207 C-to-T mutation in NEMO, leading to R-for-C substitution at position 417 in the zinc finger domain. He has had a long history of recurrent viral and bacterial sinopulmonary infections since infancy continuing into adulthood, with over thirty lifetime episodes of serious pneumonia requiring hospitalizations, which has led to bronchiectasis.At 36 years of age, he presented to the hospital for five months of progressively worsening dyspnea and wheezing, hypoxemic respiratory failure, and a 15-pound weight loss. CT imaging demonstrated increased consolidation and nodularity, and sputum culture revealed methicillinsusceptible Staphylococcus aureus and Corynebacterium pneumonia treated with vancomycin. He was incidentally found to have a new 7.5 cm left periaortic lymph node conglomerate on CT abdomen/pelvis. Lymph node biopsy showed B-cell lymphoma with plasmacytic differentiation and with increased large cells, most concerning for marginal zone lymphoma. He received eight doses of rituximab as well as radiation therapy, with subsequent improvement on imaging. Following this diagnosis, lung biopsy was obtained, demonstrating nodular fibrosis in a primarily airwaycentered distribution with patchy, focal organizing pneumonia, most consistent with fibrosing chronic organizing pneumonia, treated with high dose prednisone. However, his course had since been complicated by increasingly frequent hospitalizations for acute on chronic hypoxemic respiratory failure corresponding with superimposed respiratory infectious as well as exacerbations of his organizing pneumonia.Hematopoietic stem cell transplantation was strongly considered as this would be a definitive treatment for his NEMO syndrome, as he has multiple severe complications of his NEMO deficiency syndrome. Unfortunately, after multidisciplinary discussions, he was ultimately considered to not be a candidate given his very poor pulmonary status. The patient was started on rituximab for his organizing pneumonia and continued on antibiotic prophylaxis with immunoglobulin replacement.