CHRONIC GRANULOMATOUS DISEASE (CGD)
CHRONIC GRANULOMATOUS DISEASE (CGD)Duncan Mapeto BandaPhysiotherapy studentMalawi college of medicinePhysiotherapy department
Lecture objectivesCGD definitionEpidemiology & Causes Mode of inheritance & Genes involvedPathophysiologySigns & SymptomsDiagnosis and Treatment
CGDAn inherited disease whereby phagocytes ingest microbes but cannot kill them.Leads to formation of granulomas and recurrent infections.EpidemiologyThe hallmark of (CGD) is early onset of severe recurrent bacterial and fungal infections.The most commonly involved organs are those that serve as barriers against the entry of microorganisms from the environment, e.g. the skin, lungs, GI tract, lymph nodes, liver, and spleen.Chronic presentation of CGDGranuloma formation in the GI E.g. dysphagia, nausea, vomiting and abdominal painGranulomas, nodular masses of inflammatory tissue, form in response to persistent antigenic stimulus (chronic infections) or because of lack of negative feedback by oxygen radicals on proinflammatory cytokines.In every 140 patients with chronic granulomatous disease, 33% had GI involvementContinued...Granuloma of genitourinary (GU) Symptoms of GU obstruction include dysuria, incontinence, abdominal discomfort, and urinary retention.NB: Skin infections or granulomatous dermatitis occurs in almost two thirds of patients.Pathogenesis of CGDFungal causation occur in up to 20% of patients with CGDPneumonia is the most common presentationNB: Infections are caused mostly by catalase positive organisms, such as Aspergillus spp. or Staphylococcus spp., and are often life-threatening.Aspergillus species infection in CGD is often indolent, with mild or absent symptoms at the outset.Indolent=slow to dvelop7CausesMutation of CYBA, CYBB, NCF1,NCF2 and NCF4 genes which code for subunits of NADPH oxidase NADPH oxidase plays a role in immune systemNADPH oxidase Hydrogen peroxide (kills engulfed microbes)
Mode of inheritanceX-linked reccessive patternCYBB is located on X-chromosome More males affected than femalesHeterozygous carriersHomozygous recessive (suffers)Homozygous dominant (normal)
YX, XX respectively. 9 Continued.....Autosomal recessive patternInvolved CYBA, NCF1, NCF2 & NCF4Equal chance of occurrence in males and females No signs & symptoms in carriers10Continued....Among those with GI involvement, 89% had X91 versus 11% with autosomal recessive chronic granulomatous disease.
However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers.Erythematosus=superficial reddening of the skinPhotosensitivity=easily responding to lightAphthous=small ulcers in mouth or tongueRaynaud phenomenon=whiteness and pain in fingers wth unusual vibrations11PathophysiologyPhagocytes ingest microbes but fail to kill themKilling of microbes is mediated by NADPH oxidase also called phagocyte oxidase (phox).When this is non functioning there is a defect in the killing mechanism.Phagocyte DefectThe NADPH oxidase is a key component of human innate host defences.In phagocytes, this enzyme complex is activated to produce superoxide anion and other secondarily derived ROS (reactive oxygen species)
NADPH 2 e + 2O2 > NADP+ + H+ + 2 .O2Continued..All animals release superoxide (O2) during respirationSuperoxide dismutase (SOD) converts O2 into hydrogen peroxide (H2O2)H2O2 is used to kill pathogensSome pathogens e.g staphlococus aureaus are catalase positiveThey release catalase and O2Continued....Therefore patients with CGD experience severe recurrent bacterial and fungal infections due to accumulation of phagocytes containing ingested bacteria.Apoptosis/turnover is abnormal.
Signs & SymptomsPneumoniaProlonged infectionsskin, liver, bone & joints, etc.Hepatomegaly & splenomegalyMay develop WBC clusters
Note: Most people diagnosed during early life
17DiagnosisChest therapyNitroblue tetrazolium testHydrogen peroxide amount testTreatmentAntibiotic therapyAntifungal; itraconazole & Amphotericin BAntibacterial; TrimethoprimGranulocyte transfusions from GCSFHematopoietic stem cell transfusionsFrom a matched donorSurgery to treat abscessesGene therapy ? ? ?
Infection reduction measuresGarden exposure limitsNo swimming other than in Chlorinated waterNo Marijuana smokingHas Aspergillus spp21