Manifestations Of Chronic Granulomatous Disease Research Articles

Intrathoracic tuberculosis in the pseudotumoral and bone form as a manifestation of chronic granulomatous disease

Intrathoracic tuberculosis in the pseudotumoral and bone form as a manifestation of chronic granulomatous disease

Neonatal Manifestations of Chronic Granulomatous Disease: MAS/HLH and Necrotizing Pneumonia as Unusual Phenotypes and Review of the Literature.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI), characterized by a deficient phagocyte killing due to the inability of NADPH oxidase to produce reactive oxygen species in the phagosome. Patients with CGD suffer from severe and recurrent infections and chronic inflammatory disorders. Onset of CGD has been rarely reported in neonates and only as single case reports or small case series. We report here the cases of three newborns from two different kindreds, presenting with novel infectious and inflammatory phenotypes associated with CGD. A girl with CYBA deficiency presented with necrotizing pneumonia, requiring a prolonged antibiotic treatment and resulting in fibrotic pulmonary changes. From the second kindred, the first of two brothers developed a fatal Burkholderia multivorans sepsis and died at 24days of life. His younger brother had a diagnosis of CYBB deficiency and presented with Macrophage Activation Syndrome/Hemophagocytic Lympho-Histiocytosis (MAS/HLH) without any infection, that could be controlled with steroids. We further report the findings of a review of the literature and show that the spectrum of microorganisms causing infections in neonates with CGD is similar to that of older patients, but the clinical manifestations are more diverse, especially those related to the inflammatory syndromes. Our findings extend the spectrum of the clinical presentation of CGD to include unusual neonatal phenotypes. The recognition of the very early, potentially life-threatening manifestations of CGD is crucial for a prompt diagnosis, improvement of survival and reduction of the risk of long-term sequelae.

Infectious and inflammatory gastrointestinal manifestations of chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inborn error of immunity caused by a defect in one of the components of the NADPH oxidase complex, which is responsible for generating reactive oxygen species (ROS) during the respiratory burst in phagocytes. The absence of ROS produced by NADPH oxidase in neutrophils and in macrophages leads to greater susceptibility to certain bacterial and fungal infections, and also to inflammatory manifestations due to a deregulated inflammatory response, which suggests that the ability to adequately regulate inflammatory signaling depends on ROS produced by NADPH oxidase. The disease course in patients with X-linked CGD is more severe, with recurrent invasive infections; in contrast, patients with non-classic CGD do not present invasive bacterial or fungal infections, but have more prominent inflammatory manifestations. The most frequent gastrointestinal manifestations are stomatitis, gingivitis, chronic diarrhea, liver abscesses that are similar to inflammatory bowel disease (IBD), and granulomas that can cause obstruction or stenosis in the esophagus, stomach or intestine. It has been observed that the deficiency of p40phox and ROS (non-classic CGD) are associated with greater susceptibility to colitis and the development of severe inflammation; therefore, it is presented that these proteins participate in the resolution of inflammation. In general, the inflammatory findings in CGD, including gastrointestinal manifestations, are seldom described. In international cohorts, manifestations that are similar to IBD are reported in up to 58% of patients with CGD; however, in the only Mexican cohort, its finding is described in only 4 out of 93 patients (4.3%). In this review, we summarize the gastrointestinal clinical findings of CGD, including infectious and inflammatory manifestations, emphasizing on the latter.

Late Onset of Chronic Granulomatous Disease Revealed by Paecilomyces lilacinus Cutaneous Infection

Chronic granulomatous disease (CGD) is an inherited immunodeficiency due to defective leukocyte NADPH responsible for recurrent infections and aberrant inflammation. Mutations in the CYBB gene are responsible for the X-linked CGD and account for approximately 70% of the cases. CGD is diagnosed during childhood in males. Female carriers may have biased X-inactivation and may present with clinical manifestations depending on the level of residual NADPH oxidase activity. We report the case of a previously asymptomatic female carrier who was diagnosed at age 67 with a skin infection with the rare fungus Paecilomyces lilacinus as the first manifestation of CGD. Dihydrorhodamine 123 (DHR) activity was below 10%. Next-generation sequencing (NGS) revealed mutations in DNMT3A, ASXL1, and STAG2 suggesting that clonal hematopoiesis could be responsible for a progressive loss of NADPH oxidase activity and the late onset of X-linked CGD in this patient. Long-term follow-up of asymptomatic carrier women seems to be essential after 50 years old.

Clinical and demographic pattern of chronic granulomatous disease (CGD) from a multicenter perspective: Malaysia\u2019s experience over 26 years

BackgroundA retrospective review of clinical manifestations and demographic pattern of patients diagnosed as chronic granulomatous disease (CGD) from 7 hospitals in Malaysia. An analysis of the available database would establish clinical characteristics, diagnoses and outcome including microbiologic pattern. Studying the demography allows us to document the occurrence of CGD amongst multiethnic groups and its geographical distribution for Malaysia.MethodsData from the Malaysia Primary Immunodeficiency Network (MyPIN) with cases of CGD diagnosed from 1991 until 2016 were collated and analysed.ResultsTwenty patients were diagnosed as CGD. Males (N = 13, 65%) outnumber females (N = 7, 35%). CGD is commonest amongst the Malays (65%) followed by the Chinese (15.0%), Indians (10.0%) and natives of Borneo (10.0%), reflecting the ethnic composition of the country. The mean age of diagnosis was 3.7 years. There was a positive family history in 40% of the cases. Abscess was the main presenting feature in 16 patients (80%) with one involving the brain. Pneumonia occurred in 10 (50%) and one with complicated bronchiectasis. Catalase-positive bacteria were the most commonly isolated pathogen with Chromobacterium violaceum predominating (N = 5, 25%) with consequent high mortality (N = 4, 80%). All CGD patients with C. violaceum infection displayed CD4 + (T helper cells) lymphopenia.ConclusionThis study has shown CGD occurs in the major ethnic groups of Malaysia. To the best of our knowledge, this is the first and the largest series of chronic granulomatous disease in South East Asia which may be reflective of similar clinical pattern in the region. C. violaceum infection is associated with a higher mortality in CGD patients in Malaysia. All the CGD patients with C. violaceum infection in this patient series displayed CD4 + (T helper) lymphopenia. We recorded rare clinical manifestation of CGD viz. brain abscess and bronchiectasis.

Clinical observation of Сhronic granulomatous disease in a 6-year-old child

Chronic granulomatous disease (CGD) is a hereditary disease caused by a genetic defect of violations of oxygen — dependent mechanisms of phagocytosis. Clinical manifestations of the disease are recurrent bacterial or fungal infections of the skin, hepatic abscesses, pneumonia, osteomyelitis, sepsis, meningitis et al. Most available laboratory method for the diagnosis of CGD is the test of histochemical nitro blue tetrazolium recovery (NBT-test). Allogeneic hematopoietic stem cell transplantation is considered a radical treatment for chronic granulomatous disease. The article presents a clinical observation of the manifestation of chronic granulomatous disease with an unfavorable outcome in a child aged 6 years.

Imaging findings of pulmonary manifestations of chronic granulomatous disease in a large single center from Shanghai, China (1999\u20132018)

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation in multiple organs, especially the lung. We aimed to investigate pulmonary manifestations by computed tomography (CT). In total, 100 patients with 117 episodes of pulmonary infection were included. Chest CT scans of every episode were analyzed. Random nodules were the most common findings (79.49%), followed by ground-grass opacities (74.36%), focal consolidations (62.39%), and masses (59.83%). Cavities (12.82%) and multiple small abscesses (17.09%) could be found in the consolidations and masses. CT revealed interstitial pneumonia with tree-in-bud opacities (17.09%), interlobular septal thickening (23.08%) and emphysema (35.04%), which were more severe in the bilateral upper lobes. Mediastinal and hilar lymphadenopathy (78.63%) and axillary lymphadenopathy (65.81%) were common. Fungal infection (n = 27) was the most common and presented with multiple nodules and masses. Approximately 1/4 of fungal infections had interstitial pneumonia. In Staphylococcus aureus (n = 6) and Klebsiella pneumoniae (n = 3) infections, large areas of consolidation were common. In tuberculosis infection, the pulmonary infections were more severe and complex. For Bacillus Calmette-Guérin disease, left-sided axillary lymphadenopathy was a characteristic manifestation. CT images of CGD demonstrated variable pulmonary abnormalities. The main infectious organisms have unique imaging features.

Granulomatous inflammation in the manifestation of chronic granulomatous disease: a clinical case report

Chronic granulomatous disease is a primary immunodeficiency, characterized by a violation of the oxygen-dependent mechanisms of phagocytosis. Mutations in the genes encoding proteins of the NADPH-oxidase complex lead to a violation of the respiratory burst. Clinical manifestations are recurrent bacterial and fungal infections, and the development of granulomatous complications due to a defect in autophagy, accompanied by an increase in the level of interleukin-1 inthe blood. The treatment of this disease is continuous preventive antimicrobial therapy, and specific therapy for the treatment of granulomatous complications. Hematopoietic stem cell transplantation from an allogeneic or unrelated donor is currently considered to be only radical treatment for CGD. This article presents a clinical case of the manifestation of an X-linked form of chronic granulomatous disease with granulomatous manifestations in the absence of an infectious history. Parents patient agreed to use personal data in research and publications.

INFECTION OR INFLAMMATION? RAPIDLY PROGRESSIVE PULMONARY CONSOLIDATION IN A PATIENT WITH CHRONIC GRANULOMATOUS DISEASE

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Fever in patients with chronic granulomatous disease (CGD) poses a unique diagnostic challenge for clinicians. We present a case of progressive right middle lobe consolidation in a patient with CGD which was determined to be secondary to Burkholderia multivorans after extensive investigation. CASE PRESENTATION: A 24 year old woman with p47phox-deficient CGD, compliant with interferon and antimicrobial prophylactic therapy, was admitted for the third time in one month with fevers, dyspnea, productive cough, and pleuritic chest pain. At her first admission, imaging showed right hilar lymphadenopathy with multiple pulmonary nodules. Bronchoscopy with lavage and endobronchial ultrasound was notable for Actinomyces, and high dose amoxicillin was prescribed. She was re-admitted for persistent symptoms, with repeat imaging showing new mediastinal consolidation in the right middle lobe. Bronchoscopy with trans-bronchial biopsies were unrevealing. She was discharged on cefepime and voriconazole empirically. She was readmitted due to persistent symptoms and imaging showed worsening right middle lobe consolidation and new pulmonary nodules, and vancomycin was added. Pathology obtained from bronchoscopy with cryobiopsy showed focal interstitial non-caseating granulomas, and oral steroids were initiated for possible CGD flare. Given persistent symptoms refractory to medical therapy, right middle lobe resection was performed. Pathology showed extensive multifocal caseating granulomas, and tissue cultures showed Burkholderia multivorans, sensitive to ciprofloxacin. Follow-up CT scan one month later showed improvement in pulmonary nodules and no further consolidation. DISCUSSION: CGD is an immunodeficiency syndrome characterized by inheritable defects of NADPH oxidase, leading to the inability of phagocytic cells to destroy ingested organisms. Patients are often diagnosed in childhood due to recurrent life-threatening infections or complications from granuloma formation. Pulmonary involvement is common, and infectious etiologies such as Aspergillus are responsible for 40-85% of all lung disease in CGD patients. Noninfectious pulmonary complications include granuloma formation, which may be triggered by incompletely resolved or recurrent infection, making the distinction of sterile versus infected granulomas harder. Isolation of offending organisms is crucial, but only occurs in about 52% of cases (1). While the use of antimicrobial prophylaxis has improved mortality of CGD patients, respiratory involvement is a poor prognostic factor, rendering early identification of etiology critical. CONCLUSIONS: In patients with chronic granulomatous disease with persistent pulmonary symptoms refractory to therapy, aggressive tissue sampling including surgical biopsy should be pursued to identify etiology. Reference #1: Mahdaviani, Seyed Alireza, et al. "Pulmonary manifestations of chronic granulomatous disease.” Expert Review of Clinical Immunology 9.2 (2013): 153-160. Reference #2: Salvator, Hélène, et al. "Pulmonary manifestations in adult patients with chronic granulomatous disease.” European Respiratory Journal 45.6 (2015): 1613-1623. DISCLOSURES: No relevant relationships by Michael Agatstein, source=Web Response No relevant relationships by Deepika Kulkarni, source=Web Response No relevant relationships by Seetha Lakshmi, source=Web Response

Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series

Efficacy and safety of thalidomide in patients with inflammatory manifestations of chronic granulomatous disease: A retrospective case series

Pulmonary manifestations of chronic granulomatous disease

Chronic granulomatous disease (CGD) is an inherited disorder, characterized by defects in superoxide-generating NADPH oxidase of phagocytes. The genetic defects in CGD induce failure to activate the respiratory burst in the phagocytes, leading to severe recurrent infections and unexplained prolonged inflammatory reactions that may produce granulomatous lesions. A noble advance in curative therapy for CGD is hematopoietic stem cell transplantation. Since the most common site of involvement in CGD is the lung, the pulmonologists (pediatrics or adult) may be among the first to recognize the pattern of infection, inflammation and granuloma formation, leading to diagnosis of CGD. Pulmonologists need to be aware of different lung manifestations of CGD.

Chronic granulomatous disease presenting as aseptic ascites in a 2-year-old child.

Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected after identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children.

Advances in the diagnosis and treatment of chronic granulomatous disease

Chronic granulomatous disease (CGD), characterized 50 years ago as a primary immunodeficiency disorder of phagocytic cells (resulting in failure to kill a defined spectrum of bacteria and fungi and in concomitant chronic granulomatous inflammation) now comprises five genetic defects impairing one of the five subunits of phagocyte NADPH oxidase (Phox). Phox normally generates reactive oxygen species (ROS) engaged in intracellular and extracellular host defence and resolving accompanying inflammatory processes. 'Fatal' granulomatous disease has now changed into a chronic inflammatory condition with a median survival of 35 years and is now of interest to both paediatricians and internists. Clinical vigilance and expert knowledge are needed for early recognition and tailored treatment of this relatively rare genetic disorder. Infections by unanticipated pathogens and noncirrhotic portal hypertension need to be recognized as new CGD manifestations. Adult-onset CGD too is increasingly observed even in the elderly. Conservative treatment of fungal infections needs close monitoring due to the spread of azole resistance following extensive use of azoles in agriculture. Curative haematopoietic stem cell transplantation (HSCT) in early childhood has expanded with impressive results following use of matched, unrelated or cord blood donors and of a reduced intensity conditioning (RIC) regimen. Gene therapy, however, still has major limitations, remaining experimental. CGD is more prevalent than initially believed with a birth prevalence of 1: 120 000. As patients are increasingly diagnosed around the world and grow older, further manifestations of CGD are expected. While fungal infections have lost some threat, therapeutic research focuses on two other important aims: pharmacologic cure of chronic inflammation and long-term cure of CGD by gene therapy.

Chronic Granulomatous Disease: Lessons from a Rare Disorder

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-γ has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs).

Diffuse interstitial pneumonia and pulmonary hypertension: a novel manifestation of chronic granulomatous disease

The present authors report the case of an adult with chronic granulomatous disease who developed an unusual lung fibrosis associated with severe pulmonary hypertension. Histological analysis of a lung biopsy showed a diffuse infiltration with pigmented macrophages without granulomas, which particularly involved the pulmonary arterial and venular walls. Clinical and histological findings were suggestive of pulmonary veno-occlusive disease. Such a clinical association has not been previously described in the literature and might be due to the persistent expression of gp91phox at a very low level. In conclusion, the present case report illustrates a novel manifestation of chronic granulomatous disease.

Chest Radiographic and CT Manifestations of Chronic Granulomatous Disease in Adults

The purpose of this study was to describe the thoracic radiologic findings of chronic granulomatous disease in adults. We retrospectively analyzed the chest radiographic and CT findings in four adults with chronic granulomatous disease during five episodes of lower respiratory tract infection. Chest radiographic findings included areas of consolidation (60%), diffuse reticulonodular opacities (40%), pleural effusion (20%), and pulmonary artery enlargement (20%). CT findings included areas of consolidation (60%), pulmonary nodules in a random distribution (60%), centrilobular nodules (60%), tree-in-bud opacities (40%), areas of scarring and traction bronchiectasis (100%), emphysematous changes (75%), areas of decreased attenuation and vascularity associated with air trapping on expiratory CT (50%), mediastinal and/or hilar lymphadenopathy (60%), pulmonary artery enlargement (50%), and pleural effusion (20%). Areas of consolidation and nodules were the most prominent findings and at histologic examination were found to be associated with infection or granulomatous inflammation. The pulmonary radiologic findings of chronic granulomatous disease include consolidation, nodules, areas of scarring, traction bronchiectasis, emphysema, air trapping, mediastinal and hilar lymphadenopathy, pulmonary artery enlargement, and pleural effusion.

BASIDIOMYCETOUS FUNGAL INONOTUS TROPICALIS SACRAL OSTEOMYELITIS IN X-LINKED CHRONIC GRANULOMATOUS DISEASE

Osteomyelitis is a common clinical manifestation of chronic granulomatous disease, a disorder of phagocytic function. Fungal organisms account for a significant proportion of these infections. We describe the clinical presentation and subsequent destructive sacral osteomyelitis with a basidiomycetous mold, Inonotus tropicalis, in a patient with an X-linked chronic granulomatous disease.

Gastrointestinal (GI) Involvement in Iranian Patients with Chronic Granulomatous Disease (CGD)

RATIONALE: The objective of the study was to determine the clinical manifestations, prevalence, and consequences of GI involvement in Iranian patients with CGD. METHODS: Medical records of 57 patients (38 males and 19 females) with CGD (confirmed by nitroblue tetrazolium reduction), referred to three immunodeficiency referral centres during a 24-year period (1980-2004), were studied and abstracted for GI manifestations. RESULTS: The median age at the time of study was 14.5 years old (1 - 56 years). The median age of the first sign or symptom was 5 months (1 month - 13.75 years), and that of diagnosis was 5 years (2 months - 54.1 years), with a diagnostic delay of 33 months, on average. Twenty-four cases (42.1%) had been complicated by gastrointestinal manifestations during their course of the disease. Of those, 12 (21.1%) had diarrhea, 7 (12.3%) had oral candidiasis, 5 (8.8%) had hepatitis, 4 (7.0%) had hepatic abscess, and 2 (3.5%) had gastric outlet obstruction. Also, growth delay was detected in 6 patients (10.5%). The median age of first GI manifestation was 2 years (1 year - 12 years). In 12 patients (21.0%), GI presentations were the first manifestation of CGD. Although, the majority of GI involvement episodes were controlled by antibiotic and steroid therapy, in 83% of cases, relapse of complications were reported.Among four patients who died (7.0%), no one was reported due to GI complications. CONCLUSIONS: GI involvement is a common and recurring problem in CGD and should be considered in CGD patients with diarrhea, abdominal pain or failure to thrive.

Liver Abscesses in Children: A Single Center Experience in the Developed World

The aim of this study was to investigate the clinical and radiologic features, predisposing risk factors, and complications of children with pyogenic liver abscess (PLA) referred to a tertiary pediatric hepatology center. We analyzed our database of all children referred to our unit over a 10 year period and performed a case note review of all patients with a radiologically proven PLA. PLA was diagnosed in 15 children (7 boys), 0.5% of all referrals. They presented at a median age of 10 years (range 2 months-15 years). In three children (2 boys), PLA was the first manifestation of chronic granulomatous disease. Among the others, five had radiologic evidence of other intra-abdominal pathology (1 with subsequently proven appendicitis), and four developed portal vein thrombosis with portal hypertension. The commonest isolated pathogen was Staphylococcus aureus. Combined treatment with guided aspiration and prolonged intravenous antibiotics was successful in all patients. PLA is a rare diagnosis in children in the developed world. It may be caused by primary neutrophil disorders even in the absence of a previous history of infection. Co-existent appendicitis, intra-abdominal sepsis, and ascending pylephlebitis must be sought because these children are at risk of developing portal vein obstruction and portal hypertension. Prolonged intravenous antibiotic treatment guided by microbiologic sensitivities is highly effective.

Acremonium kiliense infection in a child with chronic granulomatous disease

Infection by unusual microorganisms can be one of the clinical manifestations of primary immunodeficiency (PID). We report on a four-month-old child with pneumonia caused by the fungus Acremonium kiliense as the first clinical manifestation of chronic granulomatous disease. We emphasize the importance of an active search for unusual organisms in immunodeficient patients, and a precise diagnosis and early institution of specific treatment against such microorganisms for the reduction of the morbidity and mortality of these patients.