Paediatric Tuberculosis: Epidemiology & Treatment PDF

Paediatric Tuberculosis ( Epidemiology & treatment) Henry Stokes Mulenga 24.11.2023 Paediatric Tuberculosis Introduction  Aetiology  Clinical stages  Epidemiology  Transmission  Pathogenesis  Clinical manifestations  Diagnosis  Mycobacterium susceptibility and sampling  Treatme...

Paediatric Tuberculosis ( Epidemiology & treatment) Henry Stokes Mulenga 24.11.2023 Paediatric Tuberculosis Introduction  Aetiology  Clinical stages  Epidemiology  Transmission  Pathogenesis  Clinical manifestations  Diagnosis  Mycobacterium susceptibility and sampling  Treatment  Prevention Paediatric Tuberculosis Clinical manifestations  Pulmonary disease  Progressive primary pulmonary disease  Reactivation tuberculosis  Pleural effusion  Pericardial disease  Lympho-haematogenous disease  Upper Respiratory tract disease  Lymph node disease  CNS disease  Cutaneous disease  Bone and joint disease Paediatric Tuberculosis Clinical manifestations (cont)  Abdominal and Gastro-intestinal disease  Genitourinary disease  Pregnancy and newborn  Perinatal disease  TB in HIV infected children Paediatric Tuberculosis Epidemiology Programmatic approach (WHO 2020) End TB strategy 2015  Reduce incidence of TB by 90%  Decrease TB mortality by 95% Stop TB partnership and WHO revised strategy 2018  Prevention of new TB cases in children  Control spread of TB in children Drug resistant TB in children  RR indicates resistance to Rifampicin  MDR indicated multi-drug resistance (Resistant to INH & R)  Extensively Drug Resistant (MDR resistant to Fluroquinolones)  Totally Drug Resistant Classification  PTB,  EPTB  DTB  EPTB more likely in children  There is usually concurrent pulmonary disease  Clinicians may fail to detect extra pulmonary disease  Disseminated TB involves the haematopoietic system or 2 or more non contiguous sites especially malnourished children  Congenital TB  Neonatal TB Paediatric Tuberculosis TB mortality  Inaccurate statistics  Estimated mortality in children is 16-24 % of all TB deaths  It is predicted that mortality would reduce by 50% with better case detection Prevalent and Emerging Risk Factors  Active TB is a 2 stage process  Exposure leading to Infection (LTBI)  Infection progressing to Active disease Paediatric Tuberculosis Barriers to childhood TB control and elimination  Health system barriers  Case finding barriers  Socio-economic barriers Paediatric Tuberculosis Health system barriers  Inequitable healthcare  Infrastructure not integrated sufficiently between health and community  Lack of programmatic linkages  Lack of commitment to LTBI detection and treatment  Lack of specific programmes targeting children and pregnant mothers  No trained Human Resource  No retention policy for trained Human Resource Paediatric Tuberculosis Case detection barriers  TB is difficult to diagnose because of difficulties in obtaining samples  Tests have low sensitivity  Training amongst physicians is not focused on TB enough and poor diagnostic tools  Structural problems  Under reporting  Over diagnosis Paediatric Tuberculosis Social economic barriers  No social income net for indigent communities  No penetrating health education programmes  Stigmatisation of TB  Lack of Trust in Healthcare system Paediatric Tuberculosis Case detection Clinical diagnosis  Clinical judgement (ability to weigh evidence against risk)  History of a contact mostly adult with PTB has high positive predictive value (PPV) in ill child.  Healthy child with history of contact should be on the LTBI care pathway.  Initial signs and symptoms PTB and EPTB  Non specific  Failure To Thrive, Irritability, Reduced playfulness, sleep disturbance  Poor appetite, vomiting and abdominal pain  Presence of chronic cough increases likelihood of TB (Odds ratio 13.8 95% CI , 2-83) indicating heterogeneity  A combination of cough, weight loss and restlessness has PPV of 80%  Clinical diagnosis > negative smear and culture results in urgent situations Paediatric Tuberculosis Case detection Conventional bacteriologic confirmation  Signs and symptoms have low specificity risking over diagnosis  Smear microscopy has low sensitivity  Cultures provide results after 2-4 weeks minimum 10 days  WHO recommends Rapid Molecular Diagnosis Paediatric Tuberculosis Case detection Xper Ultra Assay  Automated, integrated, cartridge based molecular assay  Identifies TB  Identifies Rifampicin Resistance directly from sputum  Has high sensitivity and ideal for Paediatric patients  Also performs well with Extra-Pulmonary specimens except urine and pleural fluid  Stool is now trailed Paediatric Tuberculosis Case detection Histo-pathological diagnosis  Bactereologic confirmation requires invasive sampling techniques under preferably Interventional radiology  LP  Needle aspirations  Needle biopsy  Surgical biopsy  The diagnostic histology is caseation with granuloma formation  Histology prevents under-diagnosis and misdiagnosis Paediatric Tuberculosis Case detection Biomarkers  Biological markers are biological measures of biological state  Objectively measured and evaluated  Indicator of  Normal biological processes  Pathogenic processes  Pharmacological responses  Biomarker assisted diagnosis has two advantages  Relatively easy to access specimens  Provide supportive evidence in high risk patients with negative cultures  Can allow disease monitoring and prognostication Paediatric Tuberculosis Case detection Biomarkers (cont)  Urine Lipo-arabinomannan LF point of care test  Sensitivity of 43% ; 95th CI: 69-88%  Add on test in detection of TB in children living with HIV  WHO recommends using the test in children with CD4 < 100/ mm3 in combination with clinical diagnosis  Other biomarkers awaiting adoption best used in combination are:  Micro MRA  Interleukins  Cytokines Paediatric Tuberculosis Case detection Radiological Diagnosis (plain radiography and ultrasound)  Low cost and widely available  Have low sensitivity in PTB and EPTB in children  Ultrasonography is operator dependant  CT and MRI should be considered where there is doubt Paediatric Tuberculosis Case detection Diagnostic markers of Latent TB Infection (LTBI)  Tuberculin skin test and Interferon Gamma assays unreliable in children < 4 years  Treat suspected LTBI in household contacts  Children who require testing  Refuges or internationally displaced children from HBC  Children with immuno-deficiences with uncertain contact history  Children receiving immuno-suppressants and myeloablative therapy with uncertain contact history.  Testing may help in combination with suggestive history Paediatric Tuberculosis Case detection Clinical scoring and non scoring diagnostic systems  Scoring systems:  Brazilian Ministry of Health  Kenneth Jones  Keith Edwards  Non-scoring system:  Marais criteria  BMOH used in HIV infected children suspected of TB  Sensitivity 48.3% (95% CI, 35.2%-61.6%)  Specificity 76.5% (95% CI, 62.5-87.2%)  Marais criteria  Sensitivity 84.4% (95% CI, 73.1-92.2%)  Specificity 29.8% (95% CI, 18.4-43.4%)  Paediatric Tuberculosis (Latest perspectives I: Epidemiology) Henry Stokes Mulenga 24.11.2023 Paediatric TB (treatment) Henry Stokes Mulenga 24.11.2023 Paediatric Tuberculosis Treatment  Treatment of drug-susceptible TB  Drug-susceptible PTB  Drug-susceptible EPTB  Dosing frequency Paediatric Tuberculosis Treatment of drug-susceptible TB  First line treatment consists of: Tablet H50R75Z150  For 2 months  Rifampicin (R) 10-20mg /kg, max. 600mg/day  Pyrazinamide (Z) 30-40mg / kg  Isoniazid (H) 10-15 mg / kg max. 300mg / day  Ethambutol (E) 15-25mg / kg (in areas of high HIV or Isoniazid resistance)  For next 4 months  Rifampicin (R) 10-20mg /kg, max. 600mg/day  Isoniazid (H) 10-15 mg / kg max. 300mg / day Paediatric Tuberculosis Problems associated with treating DSTB in children  Absence of therapeutic drug monitoring in resource poor settings  Suboptimal drug concentrations in FDC formulations  WHO has revised dosage range in children down to 2 years and including fast acetylators  Isoniazid 7-15mg / kg / day  In FDC if Isoniazid 15mg / kg / day is used the therapeautic dose of (Z) will be exceeded.  Rifamycin group (Rifampicin, Rifabutin and Rifampetin)  Higher doses of (R) 30-35mg / kg / day achieves better levels  Children with Co- HIV infection use Rifabutin 5mg / kg /day. Max 150- 300 mg / day in adults  Rifabutin has fewer drug interactions Paediatric Tuberculosis Problems associated with treating DSTB in children  High relapse rate noted with 4m Floroquinolene based regimen  First 2 months (2 HRptZMfx)  Isoniazid  Rifampicin  Prothionamide (pt)  Pyrazinamide  Moxiflofloxacin (Mfx)  Next 2 months  HRpt Mfx Paediatric Tuberculosis New combinations non-inferior with classical FDC (2021) 4 month combination I  First 2 months  Isoniazid (H)  Rifapentine (RPT)  Pyrazinamide (Z)  Ethambutol (E)  Next 9 weeks  RPTH Paediatric Tuberculosis New combinations non-inferior with classical FDC (2021) 4 month combination II  First 2 months  HRPTZMfx  Followed by 9 weeks  HRTPMfx Paediatric Tuberculosis Treatment of LTBI  Adults run a risk of 10 % of converting to active disease  Children < 5 years run a risk of 50% of converting to active disease  Risk is particularly high in children younger than 3years Treatment (Refer to guidelines)  Children > 2 years can be treated for 3 months with once weekly Isoniazid / Rifapentin (3HP)  Higher doses may be required Also  Four months of Rifampicin (4R)  Or Three month daily Isoniazid / Rifampicin (3 HR)  6-9 monotherapy with Isoniazid less preferred Paediatric Tuberculosis Treatment of Drug-resistant TB Core drugs  Oxazolidones (Cycloserine and Linezolid)  Imepenem-cilastin and Meropenem Paediatric Tuberculosis New drugs for drug-resistant TB  Bedaquilline for children > 3 years  Delamanid (Nitroimidazole) for 6 months intensive phase for MDR TB and XDR TB with high baseline risk for poor outcomes  Delamanid has higher sputum culture conversion and lower mortality  Delamanid can now be conditionally used in MDR and RR  Useful as adjunct in longer regimes  Pretomanid Bangladesh regimen  Intensive phase 4-6 months with Kanamycin, Moxifloxacin, Prothiamide, Clofazime, high dose Isoniazid, Pyrizinamide and Ethambutol  Plus 5 moths Continuation phase with Moxifloxacin, Clofazimine, Pyrizinamide and Ethambutol Paediatric Tuberculosis New drugs for drug-resistant TB Paediatric Tuberculosis Recommendations on treatment and care for Isoniazid Resistant TB  Only 2% of children  6 months of ((H)REZLfx) Rifampicin, Ethambutol, Pyrizinamide and Levofloxacin  Adding Streptomycin and other injectables is not recommended  Put in place surveillance of Isoniazid resistance mutations Paediatric Tuberculosis Recommendations on treatment and care for Multidrug/ Rifampicin-resistant TB  Longer MDR TB Paediatric Tuberculosis Supportive surgery especially in treatment failure  Massive haemoptysis  Bronchectasis  Bronchopulmonary fistula  Aspergilloma Paediatric Tuberculosis Adverse effects of first line treatment Rarely reported in children  Isoniazid  Rifampicin  Pyrizinamide  Ethambutol Adverse effects of second line treatment  Higher frequency with toxicity reports up to 40%  Growth failure on Fluoroquilones not frequent  Monitor QT prolongation with Bedaquilline Paediatric Tuberculosis Vulnerable populations  Human immunodeficiency and TB  Refuge children  Primary immune deficiency and TB  Newborns and TB Paediatric Tuberculosis Preventing and controlling the epidemic  Preventive therapy  BCG vaccination  Patient centred care and prevention  New developments Paediatric Tuberculosis (Epidemiology & treatment) Henry Stokes Mulenga 24.11.2023 Asthma in childhood Henry Stokes Mulenga 29.09.2023 Introduction  What is asthma  Genetics of Asthma  Role of infection in Asthma  How to diagnose and phenotype Asthma  Emergency Asthma treatment  Guideline based care of chronic Asthma  Adherence: The goal to control of Asthma  Difficult childhood Asthma  Corticosteroids still at the frontline  Prevention of Asthma Asthma in childhood What is asthma  Heterogeneous chronic inflammatory condition  Variable phenotype  Influenced by genetic and environmental conditions  Characterised by  Airway hyper-responsiveness  Airway inflammation  Variable airflow obstruction Asthma in childhood What is Asthma Hyper-Responsivity  Air way constriction in response to allergens, viral infection and exercise Airway inflammation  Oedema  Increased mucous production  Influx of inflammatory cells  Denudation of epithelial cells Variable obstruction  Airway remodelling  Proliferation of extracellular matrix proteins  Vascular hyperplasia  Irreversible structural changes  Progressive loss of pulmonary function Asthma in childhood Genetics of Asthma  Genes and environment interact to increase susceptibility to asthma  Four chromosomal regions have been identified so far:  ORMDL3 on 17q21  IL1RL/IL18R on chromosome 2q  TSLP ON 5q22  IL33 ON 9p24  The HLA in 6p21 in Asians  Variants in GLCCI 1 is associated with response to inhaled steroids  PYHIN1 Asthma in childhood Role of infection in Asthma  There is increasing evidence that rhinovirus are associated with development of asthma in childhood  In chronic Asthma, there is also a role in increasing the risk for the development of asthma for:  Mycoplasma  Chylamydia  Gut microbiota Asthma in childhood How to diagnose and phenotype Asthma  Suspect asthma in someone with  Chest tightness  Cough  Wheezes  Or episodic breathlessness  Objectively measure  Airflow obstruction with spirometry  Airway hyper-responsiveness with broncho-provocation tests  Airway inflammation with sputum quantitative assays Asthma in childhood Pulmonary physiology Pulmonary mechanics  Major function of the lungs is to exchange O2 and CO2 between atmosphere and blood  The diaphragmatic contraction creates negative intra-thoracic pressure and draws air into the lungs  During disease states the diaphragm is assisted by accessory muscles of inspiration:  External inter-costal muscles  Scalene muscles  Sterno-cleidomastoid muscles  Normally passive exhalation can be voluntarily increased by use of:  Abdominal wall muscles  Internal inter-costal muscles Asthma in childhood Pulmonary physiology Pulmonary mechanics Lung volumes and capacities  Both lung volumes during normal at rest are in mid-range inflation. Volumes  Tidal volume is the amount of air inspired with each relaxed breath  Residual volume is the amount of air left in the lungs at the end of maximal exhalation Asthma in childhood Pulmonary physiology Pulmonary mechanics Lung volumes and capacities Capacities  Functional residual capacity is the amount air left in the lungs after relaxed exhalation  Functional residual capacity maintains exchange of O2 between breaths  Total lung capacity is the volume of gas in the lungs after maximal inhalation  Vital capacity is the maximal amount of gas that expelled from the lungs  Or Vital capacity = Total Lung capacity – Residual volume Asthma in childhood Pulmonary physiology Air way resistance and obstructive airway disease  Resistance is inversely proportional to the 4th power of the radius of the airway Conditions that increase airway resistance include  Bronchospasm  Excessive airway secretions  Mucosa oedema  Airway stenosis  Foreign bodies  Loss of airway integrity as in bronchoectasis  Airway compression Asthma in childhood Pulmonary physiology Air way resistance and obstructive airway disease Conditions that increase airway resistance cause Obstructive airway disease  Obstructive airway disease causes clinical signs:  Stetor or snoring like noise is due to obstruction in the nose and / or naso-pharynx  Stridor is due to obstruction in the upper airways in the neck region  Wheeze is due to obstruction exhalation in the intra-thoracic air ways  Obstructive airway disease results in  Low flow rates  Increased Residual Volume Asthma in childhood Pulmonary physiology Airway compliance and restrictive lung disease  Compliance measures the ease with which the lungs can be inflated Conditions that decrease lung compliance  Surfactant deficiency  Pulmonary fibrosis  Pulmonary oedema  Respiratory muscle weakness (cerebral quadriplegia, myopathy, prematurity)  Pleural disease (effusion, inflammation or mass)  Thoracic stiffness (scoliosis)  Abdominal distension Conditions that decrease compliance cause restrictive airway disease Asthma in childhood Pulmonary physiology Pulmonary function testing Measuring with spirometry  Most children over 6 years can perform spirometry Performing spirometry  Patient inhales to TLC  Forcibly exhales until no more air can be exhaled What is measured as expected percentage of predicted value  Forced vital capacity (FVC)  Forced expired volume in the first second (FEV1)  Forced expiratory flow (FEF) Asthma in childhood Pulmonary physiology Pulmonary function testing Peak Expiratory Flow Rate  Can be obtained with simple hand held device  Useful for home monitoring in older children with Asthma  Highly dependent on patient’s effort Body Plethymography measures  TLC  FRC  RV Asthma in childhood How to diagnose and phenotype Asthma Measuring airflow obstruction (variable)  Spirometry measurements  Monitors response to treatment  Assesses degree of reversibility with therapeautic intervention  Measures severity of asthma exacerbation  Children over 5 can perform spirometry  Reproducible  Peak Expiratory Flow  Simpler  Inexpensive to measure asthma control at home  Less reproducible  Trial of controller medication  In younger children who cannot perform spirometry or Peak Flow Asthma in childhood Measuring airflow obstruction (variable)  Forced Expiratory Volume in first second of expiration (FEV1) / Forced Vital Capacity ratio is greater than 0.7  Reversible airflow obstruction is defined as a change of 12% in FEV1 or Peak Expiratory Flow of 200l /sec from the pre-bronchodilator value after Salbutamol  Variability is the minimum morning pre-bronchodilator peak flow over one week as a percentage of the most recent best value Asthma in childhood How to diagnose and phenotype Asthma (cont) Measurement of airway hyper-responsiveness (AHR) with broncho- provocation tests  Limitation of airflow in response to stimuli that would not affect a healthy individual  AHR is more sensitive in identifying variable airflow obstruction  Useful especially when spirometry is normal Measured by  Methacholine or histamine broncho-provocation test or 4.5% hypertonic saline or Exercise or mannitol  Result is expressed as PC20 or provocation that causes 20% decrease in FEV1 (2mg/ml is severe; 16mg/ml no reactivity) Asthma in childhood How to diagnose and phenotype Asthma (cont) Airway inflammation with sputum quantitative assays  Can be objectively assessed by sputum quantitative assay or Fe NO  FeNO reflects eosinophilic airway inflammation  FeNO provides information on those patients who will respond to corticosteroids  FeNO aids in monitoring response to therapy  FeNO aids in dose optimization  FeNO detects non-adherence to corticosteroid therapy Asthma in childhood How to diagnose and phenotype Asthma (cont) Measuring general atopic tendency  Atopy is characterised by  Elevated levels of IgE  Eosinophilia (3-10%) or absolute count of > 250 eaosinophils / mm3  Preponderance of T helper (Th) 2 cells  Preponderance of T helper (Th) 2 cytokines  Interleukin 4  Interleukin 5  Interleukin 13 Asthma in childhood How to diagnose and phenotype Asthma (cont)  Allergen skin tests  In vitro tests  Imaging tests Asthma in childhood Allergen skin tests  Test all children with persistent Asthma  Test allergens include  aeroallergens such as Pollens, Mould, Dust mites and Pet dander  Strongly correlate with bronchial allergen provocative changes  Results available within a few minutes  Test during remission of symptoms Asthma in childhood Allergen skin tests (cont) Test involves  Introducing allergen into skin via prick or inter-dermal injection  Allergen diffuses into skin  Cross linking of IgE causes mast cell degranulation and weal formation  Wheal and flare are measured in 15-20 minutes  Very sensitive for detecting allergen specific IgE Asthma in childhood How to diagnose and phenotype Asthma (cont) In-vitro serum tests  Generally less sensitive  More expensive  Require several days  Serum tests are indicated for patients  Extensive dermatitis  Who cannot discontinue medications  Who cannot adhere to skin testing Asthma in childhood How to diagnose and phenotype Asthma (cont) Chest x-ray  Useful in assessing respiratory disease in children  Perform on first episode of Asthma  Recurrent attacks of wheeze or cough to exclude anatomic abnormalities Chest x-ray determines  Lung abnormalities  Information about the bony thorax (rib and vertebral abnormalities)  The heart (cardiomegaly, pericardial effusion)  Great vessels (Rt Aortic arch, vascular rings, rib notching) Asthma in childhood How to diagnose and phenotype Asthma (cont) Chest x-ray  Obtain chest x-rays in P-A and lateral projections when possible  Obtain chest x-rays in full inspiration when possible  Flattened diaphragms and increased A-P diameter are better indicators of hyperinflation  Increased density may indicate presence blood, water mucous or tissue  Expiratory views are useful in partial bronchial obstruction because the affected lung may not deflate  Decubitus chest x-ray help differentiate pleural effusion from alveolar infiltrate Asthma in childhood How to diagnose and phenotype Asthma (cont) Phenotypes of Asthma  According to severity and response to treatments  Mild-moderate Asthma; Severe refractory Asthma or Corticosteroid sensitive asthma  According to causal or trigger factor  Atopy, Aspirin, Infection, Occupation, Exercise and Obesity Asthma in childhood How to diagnose and phenotype Asthma (cont)  According to type of airway obstruction  Brittle Asthma or Irreversible airway obstruction  According to radiological findings  Airway dilatation, bronchial wall thickening and air trapping  According to nature of airway inflammation  Eosinophilic, neutrophilic, combined mixed inflammatory, pauci- granulocytic Asthma in childhood Emergency Asthma treatment Acute asthma management involves prompt recognition of severity and treatment using:  Short Acting Beta Agonists (SABA)  Anti-cholinergics  Ipratropium bromide is a short acting anticholigernic bronchodilator  Tio-tropium is long acting and approved for children older than 6 years  Systemic Corticosteroids (SCS)  Oral prednisolone 1-2mg/ kg/ day x 5 days  Oral dexamethosone 0.6mg / kg /day x 1-2 days Asthma in childhood Emergency Asthma treatment  Children with severe exacerbation should receive:  High dose SABAs mixed with Ipratropium and SCS  Children with less severe exacerbations may benefit from SCS  Patients not responding with multiple high dose SABA should receive adjunctive therapy:  Intravenous (IV) Magnesium 50-75mg/kg  Epinephrine subcutaneously or IM  Its useful to arrange follow up and prescribe ICS Asthma in childhood Guideline-based care of Persistent Asthma  Patient-centred care whose goals are  Minimal or no chronic symptoms day or night  Minimal or no exacerbations  No limitations on activity: no school days or parent’s work missed  Minimal use of SABA  Minimal or no adverse effects of medications Asthma in childhood Guideline-based care of Persistent Asthma Long term control medications  Inhaled Corticosteroids  Leukotriene modifiers  Long acting Beta 2 agonists  Theophylline  Biologics Asthma in childhood Guideline-based care of Persistent Asthma Long term control medications Inhaled Corticosteroids  Most effective anti inflammatory agents  Early treatment with ICS reduces morbidity and mortality but does not alter natural history of Asthma  Regular use reduces:  Airway hyperactivity  Need for rescue therapy  Need for hospitalisation  Risk of death  Available as  Dry powder  Aerosol  Nebuliser solution Asthma in childhood Guideline-based care of Persistent Asthma Long term control medications (cont) Inhaled Corticosteroids (cont)  Potential side effects  Reduction in growth velocity may occur but not progressive and potentially reversible (velocity reduction by 1 cm / year)  Monitor weight and height every visit  No potential effects on  Hypothalmic-pituitory axis function  Glucose metabolism  Cataracts or glucoma  Rinse mouth after use to reduce dysphonia and oral candidiasis Asthma in childhood Long term control medications Long acting Beta 2 agonists  Relax airway smooth muscle for 12-24 hours  Do not have significant anti-inflammatory effects  Used in combination with ICS Formulations  Formoterol for use in children older than 5 years  Maintenance of asthma  Prevention of exercise induce Asthma  Rapid onset of action within 15 minutes Asthma in childhood Long term control medications Long acting Beta 2 agonists (cont)  Salmeterol approved for children > 4 years,  Action within 30 minutes  Twice daily dosing  Vilanterol  Ultra-long acting Beta 2 agonists  Approved for older patients aged 18 and above  Has advantage of once daily dosing  Combinations of ICS and LABA are available  Combinations improve adherence to treatment Asthma in childhood Long term control medications Theophylline  Its use has decline because it has limited anti-inflammatory activity  It has a narrow therapeutic window, necessitating blood levels monitoring  Can be used as add on low and medium dose inhaled corticosteroids Asthma in childhood Long term control medications Leukotriene modifiers  Leukotriens are products of arachidonic acid metabolism cascade  Potent mediators of inflammation and smooth muscle constriction Leukotriene modifiers are oral daily use  Inhibit effects of leukotrienes on airway  Two classes  Cysteinyl leukotriene receptor antagonists  Leukotriene synthesis inhibitors (Zileuton)  Cysteinyl leuckotriene receptor antagonists include  Montelukast  Zafirlukast Asthma in childhood Long term control medications Leukotriene modifiers (cont) Montelukast  Once daily as chewable granules or tablets  Children 6 moths to 5 years  4mg once daily at night  Children 6 years to 14 years  5 mg once daily at night  Children 15 years and over  10mg once daily at night  Very useful in mild asthma and exercise induced asthma Asthma in childhood Long term control medications Biologics  Genetically engineered proteins  Currently 5 have been approved for clinical use in difficult to control asthma  Omalizumab  Mepolizumab  Dupilumab  Benralizumab  Reslizumab Asthma in childhood Long term control medications Biologics (available under guidance of specialist)  Omalizumab  Humanized anti-IgE monoclonal antibody  Prevents binding of free IgE to basophils and mast cells  Given every two weeks depending on body weight and pretreatment IgE  Mepolizumab  Add on therapy in severe asthma with oesinophilic phenotype  Decreases production and survival of eosinophils Asthma in childhood Long term control medications Biologics (cont)  Dupilumab  Binds IL-4 receptor  Blocks intracellular signalling IL – 4 and IL – 13  Can administered at home  Benralizumab  Binds the IL-5 receptor  Inhibits IL – 5 activity  Induces Eosinophil apoptosis  Reslizumab has activity similar to Benralizumab  Approved for over 18s Asthma in childhood Guideline-based care of Persistent Asthma  Requirements for disease classification  History  Frequency of symptoms day or night  Use of rescue Beta agonists (Salbutamol)  Important factors not included in disease classification Present medication for asthma Frequency of exacerbation Duration of Asthma diagnosis Identification of triggers Identification of allergen sensitisation  Objective data  In office spirometry in children older than 4-7 years  Home measurements of peak flows or asthma symptoms diary Asthma in childhood Guideline-based care of Persistent Asthma Who warrants controller asthma therapy for persistent Asthma  The rules of two plus six  Children with symptoms more often than 2x/week  Using Salbutamol more than 2x/week  Awakening more than 2x/month  Using more than 2 canisters of per year of SABA  Virally induced wheezing more frequently than 6 weeks that requires bronchodilator more than 6 hourly  Presence of risk factors Asthma in childhood Guideline-based care of Persistent Asthma Classification of Asthma  Mild intermittent  Symptoms/day less than 2 days week  Symptoms/night less than 2 nights/ month  Peak flow or FEV1 over 80%  Peak flow variability less than 20%  Treatment for infants and young children  No daily treatment required  Treatment of children older than 5 years  No daily treatment required Asthma in childhood Guideline-based care of Persistent Asthma Classification of Asthma  Mild Persistent  Symptoms/day over 2 / week but less than 1/day  Symptoms/night over 2 nights/month  Peak flow or FEV1 over 80%  Peak flow variability 20-30%  Treatment of children less than 5 years  Preferred treatment: low dose corticosteroids  Alternative treatment: cromolyn or LTRA  Treatment of children over 5 years  Preferred treatment: low dose corticosteroids  Alternative treatment: LTRA, Nedrocromil Asthma in childhood Guideline-based care of Persistent Asthma Classification of Asthma  Moderate persistent  Symptoms/day daily  Symptoms / night over 1 night/ week  Peak flow or FEV1 OVER 60% to less than 80%  Peak flow variability over 30%  Treatment in children less than 5 years  Low dose ICS plus LABA or medium dose steroids plus LTRA  Treatment of children over 5 years  Low to medium dose ICS plus LABA or ICS plus LTRA Asthma in childhood Guideline-based care of Persistent Asthma Classification of Asthma  Severe persistent  Symptoms/day are continual  Symptoms/night are frequent  Peak flow or FEV1 less than 60%  Peak flow variability over 30%  Treatment for children  High dose ICS plus LABA and oral steroids if needed Asthma in childhood Guideline-based care of Persistent Asthma Steroids  Beclomethasone CFC  Low dose 86-336 micrograms/day  Medium dose 336-672 micrograms/day  Beclomethasone HFA  Low dose 80-160 micrograms/day  Medium dose 160-320 micrograms/day  Budenoside DPI  Low dose 200-400 micrograms/day  Medium dose 400-800 micrograms/day Asthma in childhood Guideline-based care of Persistent Asthma Steroids (cont) others include  Flunisolide  Fluticasone is available for children 0-4 years  Mometasone  Triamcinolone Asthma in childhood Adherence: the goal to control of Asthma  Asthma requires adequate adherence to recommendations:  Therapy  Monitoring of asthma control  Avoidance of environmental triggers  Attending follow up appointments  Poor adherence is common and associated with:  Increased healthcare use  Morbidity  Mortality  Interventions:  Patient specific education Asthma in childhood Difficult childhood Asthma Severe Asthma in adults is defined as presence of one major criteria  Need for beclomethasone higher than 800 micrograms/day or fluticasone over 400 micrograms/ day or  Need for oral corticosteroids  And at least two of the following:  The need for Long Acting Beta 2 Agonist or leukotriene antagonist in addition to inhaled corticosteroids  Asthma symptoms requiring nearly daily or nearly daily use of SABA  Persistent airway obstruction with FEV1 less than 80% predicted  One or more emergency care visits for asthma per year  3 or more oral corticosteroids bursts per year  Prompt deterioration with less than 25% reduction in oral or inhaled steroids  Near fatal asthma event in the past Asthma in childhood Difficult childhood Asthma In children the 2010 Problematic Severe Asthma in Childhood initiative group has defined severe asthma in school age children:  Still symptomatic or has exacerbation or persistent airflow obstruction in spite of prescribed  Inhaled Corticosteroids and leukotriene inhibitor  Persistent symptoms are defined as  Occurring at least 3 times per week for over 3 months  Poor quality of life  One admission to intensive care or 2 admissions to the ward in one year  Two courses of oral steroids or FEV1 less than 80% post bronchodilator Asthma in childhood Difficult childhood Asthma In preschool children severe asthma is defined when maximum treatment based on guidelines fails  Persistent of symptoms with normal pulmonary function tests  persistent symptoms associated with airflow obstruction  Persistent airflow obstruction in a child with few or no clinical symptoms Asthma in childhood Difficult childhood Asthma Managing difficult asthma  Exclude other conditions  Expiratory and inspiratory radiographs  Biopsies  Immunoglobulins  pHmetry  Sweat test  Vocal fold dysfunction  Bronchoscopy to rule out tracheal stenosis and tracheomalacia Asthma in childhood Difficult childhood Asthma Management of severe asthma  Inhaled high dose steroids 2000 micrograms/day  Oral corticosteroids 0.5 to 1mg/kg/day for 2-4 weeks  Omalizumab for children with high IgE  Theophylline  Antinfective agents  Cytotoxics Asthma in childhood Prevention of Asthma  Home environment intervention strategies to reduce morbidity in sensitised children  Education about sensitisation with appropriate asthma severity medication may be the most effective way to reduce morbidity  Efforts to reduce environmental tobacco smoke exposure are important for everyone in the house hold Asthma in childhood Henry Stokes Mulenga 29.09.2023 Urinary Tract Infections Henry Stokes Mulenga 04.12.2023 Urinary tract infections Introduction  Definition, Risk factors, Clinical impact  Pathogenesis of UTI  Diagnosis  Screening for UTI in 2-24 month infants  Screening in older children and specific populations  Atypical pathogens  Asymptomatic bacteriuria  Clinical management  Antimicrobial treatment  Work up after first febrile UTI  Recurrent UTI  Prophylactic antibiotics and other prophylactic measures  Perspectives for future management of UTI Urinary tract infections Definition  Pyelonephritis  Ascending Bacterial infection of renal parenchyma  Acute lobar nephronia  Renal abscess  Perinephric abscess  Xanthogranulomatous pyelonephritis  Cystitis  Simple symptomatic Bacterial infection limited to the bladder  Acute haemorrhagic cystitis  Eosinophilic cystitis  Interstitial cystitis Urinary tract infections Risk factors for urinary tract infection Urinary tract abnormalities  Structural  VUR  Posterior Urethral Valves  Prune belly syndrome  Uretero-pelvic junction or uretero-vesical obstruction  Megaureter  Polycystic kidney disease  Functional  Neurogenic bladder  Indwelling catheter, Immuno-suppressed state  Neonates  Uncircumcised boys  Bowel and bladder dysfunction Urinary tract infections Clinical impact Acute risk of morbidity and mortality  Urosepsis  Renal Abscess Formation  Acute Kidney Injury Chronic risk of morbidity  Acquired renal scars (10-40% after APN) leading to:  Renal insufficiency  Proteinuria  Hypertension Urinary tract infections Pathogenesis of UTI Prevention of infection  Un-directional urine flow  Complete bladder emptying  Secretion of antimicrobial proteins and peptides into the urine stream by uroethelium  Urine ionic composition  Urothelium prevents bacterial adherence Urinary tract infections Pathogenesis of UTI Source and progression of infection  Most uropathogens originate from feacal flora causing ascending infection via urethra and into the bladder  UPEC (Uropathogenic Escherichia coli) relies a set of genome-encoded virulence factors to attach and invade the uroethelium  UPEC (Uropathogenic Escherichia coli) further interfers with host immune response Urinary tract infections Pathogenesis of UTI Infecting organisms  Uropathogenic Escherichia coli (UPEC) accounts 85-90% of infections  Other enteric gram–ve bacteria  Klebsiella  Pseudomonas  Proteus  Enterobacter sp.  Citrobacter  Certain gram +ve bacteria  Staphylococcal saprophyticus  Enterococcus sp.  Rarely Staphylococcus aureus Urinary tract infections Pathogenesis of UTI Acute pyelonephritis (APN)  Not much is known about the pathogenesis of APN  Mostly its a consequence of ascending infection from the bladder  VUR (vesicoureteral reflux) confers increased susceptibility in experimental models  UPEC triggers the immune response  The consequence is tubulo-interstitial inflammation  Most instances this invasive episode is self-limited  In a subset of children it leads to renal scarring  It seems that such children are genetically predisposed (Active research area) Urinary tract infections Pathogenesis of UTI Cystitis using the UPEC model  UPEC triggers the host’s innate immune response leading to:  Production of inflammatory cytokines  Complement activation  Antimicrobial peptide secretion from urothelium  Recruitment of phagocytes  Innate immunity will in most instances get rid of infection  But also leads to collateral urothelial injury and clinical symptoms of cystitis Urinary tract infections Diagnosis of UTI Urine culture  Positive urine culture  A single pathogen at a density of greater than 50,000 colony forming units (CFUs)/ml for urine collected by catheterization or suprapubic aspiration (SPA)  Greater than 100,000,CFU/ml for a midstream, clean catch urine specimen Presence of pyuria  Microscopy  Greater than or equal to 10 wbc/mm2  Greater than or equal to 5 wbc/ high powered field (HPF)  Dipstick  Leaucocyte Esterase (LE) +ve on dipstick Urinary tract infections Screening for UTI in 2-24 month infants  Infant girls: Presence of more than 2 of the following has probability of UTI greater than 2%  White race  Age less than 12 months  Fever greater than 48 hours  No other apparent fever source  Fever greater or equal to 39 c  Circumcised infant boys presence of 2 or more of the following:  Non black race  Fever greater than 24hours  No other apparent source  Fever greater or equal to 39 c Urinary tract infections Screening for UTI in older children  Screen for UTI with or without fever in presence of  Dysuria  Urgency and frequency  Cloudy urine  Abdominal or flank pain Urinary tract infections Screening in specific populations  Screening should be done in children with fever without source  Urinary tract abnormalities  Hydronephrosis  VUR  MCKD  Neurogenic bladder and voiding dysfunction  In non-verbal children cognitive disabilities Urinary tract infections Summary of UTI diagnosis Test Sensitivity Specificity Leukocyte esterase test 83 78 Nitrite test 53 98 Leukocyte esterase and 93 72 nitrite positive Microscopy (WBC) 73 81 Microscopy (Bacteria) 81 83 LE, Nitrite or 99.8 70 microscopy positive Urinary tract infections Diagnosis: some caveats Nitrites  Very specific for UTI but not always present  It can take up to 4 hours for organisms to reduce Nitrates to Nitrites  Not all uropathogenic organism reduce nitrates giving Nitrites low sensitivity Leucocyte Esterase  LE has high sensitivity  Lower incidence of pyuria in Klebsiella sp and Pseudomonas aeruginosa  Even so, LE remains the mainstay for UTI diagnosis Urinary tract infections Diagnosis: some caveats (cont) Urine microscopy  Very good at diagnosing pyuria, bacteriuria and haematuria  Microscopy is not readily available in clinical settings  Its not required for diagnosis of UTI  The presence of symptoms of cystitis, the presence of bacteria in a fresh uncentrifuged specimen of urine in combination with Gram stain is also reliable test to identify UTI Sterile Pyuria could be caused by:  Kawasaki’s disease  Glomerulonephritis  Acute interstitial nephritis  Appendicitis  Intense exercise Urinary tract infections Diagnosis: Urine culture  Send sample collected by clean catch, Catheterization or Suprapubically.  Growth happens within 24-48 hours  Sensitivities may take another 24-36 hours  Prior antibiotic treatment may give false negative and one may rely more on UA. Urinary tract infections Diagnosis: Urine culture in intermittent clean catheterization  Asymptomatic colonization is very common  Cultures may grow up to 100000 CFU  Multiple organisms may be isolated  Screen when there is high index of suspicion  UTI is diagnosed:  if patient has 2 or more symptoms  Has greater than 10WBC/HPF  Has grown over 100000 CFU/ML of a single organism Urinary tract infections Diagnosis: Atypical uropathogens  Viral cystitis  Adenovirus in immuno-competent patients  Polyomavirus in immuno-compromised patients  Gross haematuria  Dysuria  Abdominal discomfort  Schistosomiasis  Cystitis  Terminal haematuria  Fungal cystitis  Indwelling catheters  Immuno-compromised children Urinary tract infections Diagnosis: Asymptomatic bacteriuria  Between 0-10% of children with ABU will develop UTI  Screening for ABU is not recommended Urinary tract infections Clinical management Antimicrobial treatment  Start treatment if suspicion of UTI high and UA (urinalysis) is LE +ve with or without Nitrites.  Initially base on local sensitivity and resistance patterns  Adjust based on urine culture and sensitivity  Treat for 7-14 days Parenteral therapy  Acutely ill child should receive IV antibiotics for 2-4 days  Children with renal or perinephric abscess should have IV + surgery  Immunocompromised children  Children with indwelling catheter Urinary tract infections Choice of antibiotics Antibiotic Recommended Dosing Maximum Dose Amoxacillin- 20-40mg/kg/day in 3 doses 500mg/dose clavulanate Trimethoprin (TMP)- 2-24 months : 6-12 mg TMP/kg/d. 160mg/kg sulfamethoxazole > 24 months : 8mg TMP/kg/d in 2 doses Nitrofurantoin 5-7mg/kg/ in 4 doses 100mg/dose Urinary tract infections Choice of antibiotics (cont) Antibiotic Recommended dosing Maximum dose Cephalexin 50-100mg/kg/d in 4 doses daily > 15 years: 500mg X 2 daily Cefpodoxime 10mg/kg/d in 2 doses Cefixime 8mg/kg/d once daily 400mg/d Cefuroxime 20-30mg/kg/d in 2 doses 500mg/dose Urinary tract infections Important considerations  24% of E.coli is resistant to Trimethoprin-sulfamethoxazole  45% resistant to Ampicillin  Less than 10% resistant to Cephalosporins, Amoxacillin-Clavulanate, Ciprofloxacillin and Nitrofurantoin  Nitrofurantoin is good for afebrile cystitis  Discontinue empiric antibiotics with urine culture shows no growth after 48 hours Multi-drug resistant organisms  Commonly found in Hospital Acquired Infections  Children with Urinary Tract Abnormalities  Children with indwelling catheters  Children who have received antibiotics Urinary tract infections Work up after first febrile UTI Imaging  2-24 months  Use RBUS to evaluate renal parenchyma, renal size and urinary tract abnormalities  RBUS should be done after 4-6 weeks of completion of treatment  Do RBUS within 48 hours if child very ill or to rule pyonephrosis or if no improvement with IV antibiotics  If Vesical-Ureteric Reflux is diagnosed proceed to Voiding Cysto-Urethrogram (VCUG)  Consider DMSA to identify renal scaring Urinary tract infections Imaging Recurrent UTI  Review history  Carry out thorough examination  Arrange for VCUG  DMSA  Referral to a Nephrologist Urinary tract infections Prophylactic antibiotics  Select patients carefully for antibiotic prophylaxis  Children with recurrent UTI and reflux could be considered  Currently there is an unclear role for Cranberry juice  Acidify urine by increasing excretion of hippuric acid  Prevent adhesion of UPEC to uro-thelial cells  Larger studies needed Urinary tract infections Perspectives for future management of UTI Early and accurate diagnosis to limit antibiotic overusage  Mass spectrometry  Nucleic acid testing Disrupting host-pathogen interaction  Mannosides disrupt type I piliated E.coli and mannosylated receptors on the bladder mucosa surface Genetics  Could identify children at risk of UTI recurrence  Such as low DEFA1A3 gene copy number identifies patients at risk breakthrough UTI while on prophylaxis Urinary Tract Infections Henry Stokes Mulenga 04.12.2023 Hypertension in children Henry Stokes Mulenga 04.12.2-23 Introduction  Physiology of normal blood pressure  Definition and diagnosis of Hypertension  Casual blood pressure  Ambulatory blood pressure  Epidemiology  Primary hypertension  Secondary hypertension  Evaluation  Physical examination  Diagnostic studies  Treatment of hypertension Physiology of normal blood pressure  New guidelines for detection, evaluation and management of hypertension (Pediatrics, 2017)  Definition and diagnosis of Hypertension BP classification Children aged 1-12 years Everyone equal or (percentile) over 13 years old (mm Hg) Normotensive 30g in 24 hours  Podocyte is injured in most cases of heavy proteinuria  Suspect glomerular disease if Upro/Ucreat is over 1  Or significant proteinuria (major protein albumin) accompanied by  Hypertension  Haematuria with sediment  Oedema  Renal dysfunction Nephrotic syndrome in Children Evaluation of tubular-interstitial function Tubular Proteinuria  Low grade fixed proteinuria (Uprot / Ucreat = 0.2 to 1.0)  In tubular proteinuria little or no albumin is present  Abnormal pH  Abnormal urinary glucose  PT injury may result in Potassium and Phosphate wasting  DT injury may result in Hyperkaleamia  May be associated with pyuria and eosinophiluria Other investigations  C3 and C4 complement Nephrotic syndrome in Children Evaluation of vascular function Measurement of BP  BP = Cardiac output x total peripheral resistance  Peripheral resistance is determined in part by:  Activation of sympathetic nervous system and catecholamine release  Activation of Renin-Angiotensin-Aldostrone in response to decreased renal blood flow Nephrotic syndrome in Children Technique for BP measurement Steps Action Ideal conditions 1. No stimulant medication 2. Measure BP in relaxed environment 3. Allow 5 minutes rest period measurement Positioning 1. Patient seated with back supported and feet on the floor 2. Right arm supported and ante-cubital fossa at level of the heart Method 1. Perform measurement by auscultatory method 2. Stethoscope should be placed over the brachial pulse, proximal and medial to cubital fossa below bottom edge of the cuff Cuff 1. Apply cuff to bare skin 2. Bladder width > 40% and length cover 80-100 %MC Confirm 1. Take blood pressure in all 4 limbs and recheck BP on repeat visits 2. Consider ambulatory BP monitoring Nephrotic syndrome in Children BP classification Children aged 1-12 years Equal to over 13 BP classification (Percentile) years (mmHg) Normotensive < 90th & < 120/80 < 120 / < 80 Elevated BP Equal or over 90th or 120/ 80 to < 120-129 / < 80 95th Stage 1 Equal or over 95th + 11 mm Hg or 130-139 / 80-89 Hypertension 130 / 80 to 139 / 89 (lower) Stage 2 Equal or over 95th + 12 mmHg Equal or over 140 / Hypertension Or Equal to over 140 / 90 (lower) 90 Nephrotic syndrome in Children Evaluation of anatomical structure of urinary tract  Renal ultrasound (Kidney and bladder)  Kidney size  Urinary tract dilatation  Cysts, stones and masses unless very small  Pulsed Doppler Studies  Arterial and venous blood flow  Provide evidence of renal artery stenosis or renal vein thrombosis  Voiding cysto-urthrogram  Detects vesico-ureteral reflux and evaluates urethra  CT and MRI  Radionuclide studies  Renal Biopsy Nephrotic syndrome in Children Fixed Proteinuria Nephrotic range proteinuria  Proteinuria over 3.5g/24 hours  Uprot/Ucreat over 2  Hypo-albumineamia equal to or less than 25g/ L  Oedema  Hyperlipideamia (Cholesterol > 2g/L) Nephrotic syndrome in Children Causes of Nephrotic Syndrome  Idiopathic nephrotic syndrome  Genetic disorders  Congenital nephrotic syndrome  Secondary causes  Infections  Drugs  Allergic and immunologic disorders  Associated with malignancy  Glomerular hyperfiltration Nephrotic syndrome in Children Classification Genetic disorders Genetic disorder Age at onset Finnish type congential NS Infancy Diffuse mesangial sclerosis Infancy Early onset autosomal recessive SRNS Infancy and early childhood Late onset SRNS Late childhood and adolescence Nephrotic syndrome in Children Classification Syndromic genetic disorders Syndromic genetic disorders Age at onset Denys-Drash and Wilm’s tumour, Infancy Aniridia, Genital Anomalies and Intellectual Disability (WAGR) Pierson syndrome Infancy Galloway- Mowat Syndrome Infancy Schimke Immuno-osseus dysplasia Childhood Frasier Syndrome Childhood Nephrotic syndrome in Children Classification Idiopathic (Histologic classification) Idiopathic (Histologic classification) Age at onset MCNS Early childhood to adolescence FSGS Early childhood to adolescence MN Late childhood and adolescence MPGN Late childhood and adolescence Nephrotic syndrome in Children Classification Other conditions Condition Age at onset Congenital syphilis and Infancy toxoplasmosis Hepatitis B and C Variable HIV -1 Variable Malaria Variable SLE Late childhood and adolescence Nephrotic syndrome in Children Classification Other conditions Condition Age at onset Glomerular Hyperfiltration Variable Sickle Cell Disease Oligomeganephronia Morbid obesity Malignancy Variable Lymphoma Leukaemia Drugs Variable Non- steroidal anti-inflammatory drugs Lithium Pamidronate Nephrotic syndrome in Children Primary and secondary forms of Nephrotic Syndrome Form Examples Primary 1. Minimal change NS (MCNS) 2. Primary focal segmental glomerulo-sclerosis (FSGS) 3. Idiopathic membranous nephropathy 4. Hereditary NS (Congenital NS, Infantile NS) Nephrotic syndrome in Children Primary and secondary forms of Nephrotic Syndrome Form Examples Secondary Systemic Lupus Erythematosus and other glomerulonephritides (e.g. MPGN, PIGN) IgA vasculitis Chronic Infections (HIV, Malaria, Hepatitis B& C Diabetes Allergic Interstitial Nephritis Malignancies Amyloidosis Nephrotic syndrome in Children Summary of Classification  Age of presentation  Congenital (first 3 months of life)  Infantile (4-12 moths)  Childhood ( > 12 months)  Late childhood ( > 5 years)  Adolescence ( > 12 years)  Idiopathic vs. Secondary  Genetic vs. Acquired  Histology (e.g. MCD, FSGS)  Steroid sensitive vs. Steroid resistance Nephrotic syndrome in Children Primary and secondary forms of Nephrotic Syndrome  Accounts for 90% of all cases of Nephrotic syndrome  Primary glomerular disease  Multiple histological types  Minimal Change Nephrotic Syndrome (MCNS)  MP  FSGS  MN  MPGN  MCNS accounts for 85%  More than 95% of children with MCNS respond steroids Nephrotic syndrome in Children Clinical manifestations  Facial and peri-orbital oedema  Progresses to wide spread oedema  Initial presentation often follows on a trigger such as infection  Bowel wall oedema causes anorexia, malaise, abdominal pain and diarrhoea  Ascites and pleural effusion will lead to breathlessness  Usually there is no haematuria, renal dysfunction or hypertension Classic features of nephrotic syndrome  Proteinuria  Hypoalbuminaemia  Oedema  Hyperlipideamia Nephrotic syndrome in Children Clinical evaluation  History and physical examination  To identify secondary causes of NS and complications  Diagnostic evaluation is dictated by findings on  History and physical examination  Response steroids History  Age  Family history  SLE such as joint pain, stiffness and swelling, photosensitivity  Risk factors for infection  Inquiry about possible complications  Thrombosis  Infection  Abdominal pain Nephrotic syndrome in Children Clinical evaluation Physical examination  Wt, Ht, Abdominal girth , BP  Dysmorphism, anaemia, pallor, jaundice  Skin examination for SLE  Hepatosplenomegaly  Surveillance for complications  RS  CNS  CVS  GIT for peritonitis, Hepatosplenomegaly Nephrotic syndrome in Children Diagnosis In all children:  First morning Uprot / Ucreat  Serum urea and electrolytes  Creatinine: Elevated Creatinine not related to Volume depletion is common in FSGS and Secondary NS  Serum albumin level  Complement levels C3, C4  Gen Expert  Cholesterol levels  Chest x-ray Nephrotic syndrome in Children Diagnosis In older children over 10 years  Complement C3, C4 level  Antinuclear antibody  Double stranded DNA  Hepatitis B and C  HIV in high risk populations  Genetic testing  Kidney biopsy for those older than 12 years and SR Nephrotic syndrome in Children Treatment Predinisolone  60mg/ m2/day or 2mg/kg/day to max 60mg daily  For 4-6 weeks  Then alternate day starting at 40mg/m2 or 1.5mg/kg  For 8 weeks to 5 months  At least 12 weeks of steroid treatment Response  Remission within 4 weeks of treatment  Relapse abnormal urine by 3 consecutive days  Frequent relapser  Steroid dependent  Steroid resistant Nephrotic syndrome in Children Managing clinical sequelae of Nephrotic Syndrome  Oedema  Dyslipidemia  Infections  Thromboembolism  Obesity and Growth Nephrotic syndrome in Children Implications of steroid resistance Steroid Resistant Nephrotic syndrome:  50% risk of ESKD within 5 years  Persistent Nephrotic syndrome is associated:  Poor quality of life  Hypertension  Serious infection  Thrombo-embolic events Nephrotic syndrome in Children Alternative Therapies Candidates for alternative therapies  Steroid Dependent (SD) patients  Frequent Relapsers (FR)  Steroid Resistant (SR) patients Nephrotic syndrome in Children Alternative Therapies Drug Indication Caveats Cyclophosphamide FR; SD Neutropenia, 2mg/kg x 8-12 weeks Disseminated Varicella etc Calcineurin inhibitors SR Monitor for Hypertension etc Mycophenolate mofetil SD , FR Rituximab SD and SR Nephrotic Syndrome in Children Henry Stokes Mulenga 27.05.2024 Infection Related Glomerulonephritis Henry Stokes Mulenga 24.05.2024 Infection Related Glomerulonephritis Introduction and objectives. At the end of the lecture student doctors will be able to define and list the causes of haematuria, describe the course of APIGN, take a detailed history of APIGN and carry out a thorough examination of a patient with suspected APIGN and construct a management plan. Infection Related Glomerulonephritis Contents  Haematuria  Macroscopic haematuria  Microscopic haematuria  Definition of Acute Post Infectious Glomerulonephritis (APIGN).  Clinical presentation of Acute Post Streptococcal Glomerulonephritis (APSGN)  Diagnostic evaluation  Management and treatment  Other Infectious causes associated with APIGN  Endocarditis  Shunts  Hepatitis B and C  Outcomes Infection Related Glomerulonephritis Haematuria  Red blood cells are required in urine for diagnosis of haematuria.  Haematuria is either macroscopic or microscopic  More than 3-5 RBC / HPF is abnormal  Urine sediment with RBC casts or dysmorphic RBCs suggests Glomerulo- nephritis  Fresh specimen urine is preferable to avoid false negatives as a result of RBC lysis  Rule out exogenous blood such as menstruation or Munchhausen syndrome Infection Related Glomerulonephritis Haematuria Differential diagnosis macroscopic haematuria (cont) Causes of change in urine from yellow to pink or red  Blood as little as 1ml blood / 1000ml of urine  Other substances  Medications (Rifampicin, Nitrofurantoin, Metronidazole, Triamterene, Propofol and Senna)  Foods (Food dyes, Beetroot, Black berries, Rhubarb, Fava beans)  Presence of Heme (Haemoglobinuria, Myoglobinuria) Infection Related Glomerulonephritis Haematuria Differential diagnosis macroscopic (gross) haematuria Macroscopic haematuria is not frequent but it is important Factitious or Non Renal Conditions  Agents that change colour or urine  Red diaper syndrome (urate crystals, gastroenteritis due to Serratia marcescenes)  Pathologic haemoglobulinuria due haemolytic anaemia  Pathologic myoglobinuria from rhabdomyolysis Infection Related Glomerulonephritis Haematuria Differential diagnosis macroscopic haematuria Upper Urinary tract  Post-infectious glomerulo-nephritis (PIGN),  IgA nephropathy  Vascular (IgA Vasculitis previously called HSP), Renal Vein thrombosis  Interstitial nephritis  Toxin mediated injury Infection Related Glomerulonephritis Haematuria Differential diagnosis macroscopic haematuria Lower Urinary tract  Infection ( Viral, bacterial and parasitic)  Trauma (Trauma of urethra)  Stones (Nephrolithisis)  Obstruction  Cystic diseases  Malignancy Infection Related Glomerulonephritis Haematuria Microscopic Differential diagnosis of microscopic haematuria  Common: 3-5% on screening though most of it is self limiting  Symptomatic microscopic haematuria  Dysuria, urgency or frequency suggests infection or urethral bladder irritation  Presence of proteinuria with Urine Protein / Creatinine ratio greater than 0.2mg/mg (or 0.5mg /mg in an infant) prompt referral to Paediatric nephrologist for management of glomerulo-nephritis Infection Related Glomerulonephritis Haematuria Differential diagnosis of microscopic haematuria (cont)  Similarly presence of hypertension should prompt referral for investigation  Other common causes are:  Thin basement membrane nephropathy (Benign familial haematuria)  Alport syndrome  Hypercalciuria Infection Related Glomerulonephritis Work up of microscopic haematuria Multiple urinalysis positive Confirm RBC presence with microscopy Positive urine culture Transient haematuria Treat as UTI Negative urine culture Monitor transient haematuria Differential diagnosis up to 1 year Persistent Urinary RBCs Investigate Absent: transient haematuria Infection Related Glomerulonephritis Haematuria Differential diagnosis of microscopic haematuria  Common  Hyperculciuria  Basement membrane nephropathy (Begnin familial haematuria)  Other  Alport syndrome  Congenital abnormalities of urinary tract  IgA Nephropathy  Malignancy  Nephrolithiasis  Post infectious glomerulonephritis  Sickle cell trait / sickle cell disease  Nutcracker syndrome Infection Related Glomerulonephritis Haematuria Investigations to consider  Urine Calcium to urine Creatinine ratio  Urine Protein to urine Creatinine ratio  Test first degree relatives for microscopic haematuria  Hb electrophoresis to rule out sickle cell anaemia and sickle cell trait  Blood chemistry, serum albumin  C3 and C4 compliment levels  Complete blood count  Renal ultrasound  Renal biopsy in selected cases Infection Related Glomerulonephritis Acute Post Infectious Glomerulo-nephritis (APIGN) Definition  Tea or cola-coloured urine  Oedema usually localised or anasarca  High blood pressure may escalate into hypertensive crisis  APIGN accounts for 20% of Acute Renal Failure admissions Infection Related Glomerulonephritis Acute Post Infectious Glomerulo-nephritis (APIGN)  History of recent infection  Most commonly Group A beta-hemolytic streptococci throat or skin  Symptoms begin 1-2 weeks after throat infection  Symptoms begin 3-5 weeks after skin infection Other implicated organisms  Staphylococcal infections  Gram –negative bacteria  Viral  Fungal  Parasitic Infection Related Glomerulonephritis Acute Post Infectious Glomerulo-nephritis (APIGN) Pathogenesis  Infection triggers cross reacting antibodies with host antigens  Sera often contains circulating antibodies to both collagen and laminin components of the basement membrane  Certain strains are more likely to cause APSGM because of:  Nephritis associated plasmin receptor  Streptococcal pyrogenic exotoxin B  Streptococcal neuramidases enzymatically alter host immunoglobulins Infection Related Glomerulonephritis Acute Post Infectious Glomerulo-nephritis (APIGN) Pathogenesis  Antigen- antibody complexes form in  Circulation which are later deposited  In situ by binding to antigen already present in the glomerulus  Antigen-antibody complexes deposit in the glomelurar capillary wall  Antigen-antibody complexes activates complement cascade and coagulation pathways  Components such as C3 and C4 of the compliment are used up Infection Related Glomerulonephritis Acute Post Infectious Glomerulonephritis (APIGN) Clinical presentation  School-aged mean age 6-8 years range 4-14 years  Male preponderance  At infection may present with low grade fever, malaise and poor appetite  After a latent period  70% present with macroscopic haematuria  All children have microscopic haematuria Infection Related Glomerulonephritis Acute Post Infectious Glomerulo-nephritis (APIGN) Clinical presentation due to salt and water retention  Localised oedema (peri-orbital or pedal) or Anasarca  Hypertension with high probability of hypertensive crisis Classic findings in PSGN  Decreased renal function (Elevated serum creatinine)  RBC casts in urine  Sub-nephrotic proteinuria  Decreased C3 compliment  Positive Anti-streptolysin and Anti-Dnase B antibodies  Minority may present with overt Renal Failure and Nephrotic range proteinuria Infection Related Glomerulonephritis Immunoglobulin A Nephropathy  Most common primary glomerulo-nephritis world wide  Highest incidence in East Asian and Caucasian populations  45 % of primary glomerulonephritis is IgA nephropathy  IgA is rare among black populations  Usually presents in second decade of life though it does affect children mostly boys Pathogenesis  Complex involving abnormal IgA subclass glycosylation  Glactose deficient immune complexes deposit in renal mesangium  Proinflammatory factors lead to glomerular and tubular damage through activation of alternative pathway Infection Related Glomerulonephritis Immunoglobulin A Nephropathy Clinical presentation  Recurrent gross haematuria in 40-55%  Recurrent microscopic haematuria and non-nephrotic range proteinuria in 30- 40%  A small percentage present with Nephrotic syndrome or RPGN  Triggered by an URTI or gut mucosa infection  Haematuria is evident within a few days of infection unlike PSGN Diagnosis  Renal biopsy Treatment  Treat hypertension and proteinuria with ACEI and ARBs slows down progression Infection Related Glomerulonephritis Vasculitides  Rare  Kawasaki disease , sterile pyuria may present with haematuria  Immunoglobulin A Vasculitis or HSP are important  Abdominal pain  Arthritis / arthralgia  Non thrombocytopenic palpable purpura of buttocks and legs  About 20% have renal involvement  Haematuria (microscopic more often than macroscopic) and subnephrotic proteinuria  Less commonly NS, Hypertension and Renal Insufficiency Treatment of Ig A vasculitis  Spontaneous resolution  Corticosteroids may reduce abdominal pain  ACEIs / ARB for proteinuria > 0.5g / day for 6 months  For NS or Cresentric Nephritis use Intravenous methylpred and then oral steroids Infection Related Glomerulonephritis Infection Related Glomerulonephritis Evaluation  Urine and blood work  Haematuria  Urine protein/creatinine ratio  Decreased renal function  Low C3 rebounds within 6-8 weeks  ASOtitre increases 1 week after infection and peaks at 3-5 weeks  Anti Dnase B increases at 2 weeks after infection and peaks at 6-8 weeks  Imaging  No clear role  Renal biopsy  Wait for three months Infection Related Glomerulonephritis Management and treatment Supportive care and monitoring  Treat identified pathogen  Monitor development of Hypertension and renal impairment.  Avoid further exposure to nephrotoxic drugs or prolonged periods of volume depletion Infection Related Glomerulonephritis Management and treatment Supportive care and monitoring Hypertension  Monitor blood pressure all the time, hypertensive crisis can occur at any time  Admit to hospital all children with hypertension, severe oedema and renal impairment  Use diuretics  Chlorothiazide, hydrochlorothiazide  Or combination of diuretic and calcium channel blocker  Amilodipine, felodipine, Nefedipine  Avoid or use with caution Angiotensin Converting Enzyme Inhibitors (ACEI )  Captopril, Enalapril, Lisinopril  and Angiotensin Receptor Blockers (ARB)  Losartan, Valsartan, Candesartan Infection Related Glomerulonephritis Management and treatment Supportive care and monitoring  Dialysis is indicated  Severe renal impairment  Volume excess  Electrolyte imbalance that is difficult to manage  Consider steroids in RPGN  Consider plasma exchange in RPGN Infection Related Glomerulonephritis Other infectious causes associated with APIGN  Bacterial  Helminthic  Protozoal  Fungal  Viral Infection Related Glomerulonephritis Other Infectious causes associated with APIGN  Nephritis associated with endocarditis  Shunts  Hepatitis Infection Related Glomerulonephritis Outcomes Outcome is good in uncomplicated APIGN  Most common initial complication is hypertension  Most patients will have normal compliment within 3 months  By 3 years after diagnosis very few patients have proteinuria  By 4 years after diagnosis very few patients have haematuria Infection Related Glomerulonephritis Outcomes Outcome is good in uncomplicated APIGN  Some children need dialysis and a few of these progress to end stage renal failure  Especially those with IgA Nephropathy and other Chronic GN  Presence of persistent and heavy proteinuria, hypertension, decreased renal function are associated with poor outcomes  Asymptomatic or suspected Thin Basement Disease has excellent prognosis  However long term follow up is required yearly urinalysis and BP measurement is required to exclude progressive disease Infection Related Glomerulonephritis Henry Stokes Mulenga 24.05.2024 Challenges of managing chronic kidney disease in children (CKD) Henry Stokes Mulenga 28.05.2024 Introduction  Definitions  Aetiology  Kidney development and chronic kidney disease  Clinical evaluation of renal function to monitor chronic kidney disease  Chronic kidney disease stages  Presentation and screening  Management of different aspects of chronic kidney disease (CKD)  Summary Management of chronic kidney disease Definitions  Chronic Kidney Disease (CKD)is the outcome of sustained damage of renal parenchyma leading to long term deterioration of renal function.  Chronic deterioration of renal function will gradually result in End Stage Renal Disease (ERSD).  ERSD is uniformly fatal without renal replacement (dialysis or renal transplant therapy) Management of chronic kidney disease Chronic Kidney Disease 1. Kidney damage for 3 months or more with or without decreased GFR Abnormalities in composition of blood or urine Abnormalities in imaging tests Abnormalities in kidney biopsy 2. GFR equal or less than 60 ml/min/1.73 m2 for equal or over three months with or without other signs of kidney damage Management of chronic kidney disease CKD staging based on GFR (KDIGO) CKD stage GFR (ml/min/1.73 m2) Terms (in children older than 2 = 0.43 x height (cm) years) /serum creatinine (mg/dl) G1 Equal to or over 90 Normal or High G2 60 - 89 Mildly decreased G3a 45 - 59 Mildly to Moderately decreased G3b 30 - 44 Moderately to severely decreased G4 15 - 29 Severely decreased G5 135 ml / min / 1.73 m2  Proteinuria  Hypertension  Hyperphosphateamia  Hyperlipideamia Management of chronic kidney disease Pathophysiology Manifestation Mechanism Accumulation of nitrogenous waste Decrease in glomerular filtration rate products Acidosis Decreased ammonia synthesis, Impaired absorption of bicarbonate. Decreased net acid excretion Sodium wasting Solute diuresis. Tubular damage Urine concentrating defect Solute diuresis. Tubular damage Management of chronic kidney disease Pathophysiology Manifestation Mechanism Hyper-kaleamia Decrease in GFR. Metabolic acidosis. Excessive K+ intake Hypo-reninemic hypo-aldosteronism Renal Osteo-dystrophy Impaired 1,25 production. Hyper- phosphatemia. Hypo-calceamia Secondary hyperparathyroidism Growth restriction Inadequate caloric intake. Renal osteodystrophy. Metabolic acidosis. Anaemia. Growth hormone resistance Management of chronic kidney disease Pathophysiology (cont) Manifestation Mechanism Anaemia Decreased erythropoietin production. Iron, B12 & Folate deficiency. Decreased RBC life span Bleeding tendency Defective platelet function Infection Defective neutrophil function. Impaired immunity. Catheter sepsis Learning difficulties Hypertension. Low birth weight Feeding difficulties Gastro-oesophageal function. Dysmotility Management of chronic kidney disease Pathophysiology (cont) Manifestation Mechanism Hypertension Volume overload. Renin over- production Hyper-lipidemia Decreased plasma lipoprotein lipase activity. Cardio-myopathy Hypertension. Anaemia. Fluid overload Glucose intolerance Tissue insulin resistance Management of chronic kidney disease Presentation and screening  Antenatal presentation  Abnormal ultrasound  Oligo-hydramnios  Polyhydramnios  Many children with CKD have abnormal ultrasound  Bilateral small with thinned cortices suggests GN  Unilateral small kidney may indicate Arterial disease  Clubbed calyces with cortical scars may suggest reflux disease  Enlarged cystic kidneys may suggest KCD Management of chronic kidney disease Presentation and screening (cont)  Older children with Renal Anomalies  If missed they may present with polyuria, growth impairment, abnormal creatinine or abnormal incidental ultrasound  Or may be asymptomatic  Or present with chronic uraemia  Anorexia and Vomiting  Cognitive dysfunction and confusion  Ureamic pericarditis and pruritus  Chronic anaeamia  Children with glomerular disease  High BP, Oedema or incidental finding of proteinuria Management of chronic kidney disease Presentation and screening Presentation Pathophysiology Appearance Pallor secondary to anaemia Shortness of breath Fluid overload. Anaemia. Cardiomyopathy. Occult Ischeamic heart disease Itch and cramps Common in advanced CKD Cramps are worse at night Management of chronic kidney disease Presentation and screening Presentation Pathophysiology Haematuria Glomerular bleeding. Microscopy will show deformed cells Proteinuria Tubular damage results in low grade proteinuria 3.5g Peripheral oedema Due to sodium retention Hypo-albumineamia due to NS Challenges of managing chronic kidney disease in children (CKD) Henry Stokes Mulenga 28.05.2024 Management of chronic kidney disease Specific medical conditions making the spectrum CKD  Mineral and Bone Disorder  Metabolic acidosis  Potassium balance disorders  Sodium balance and intra-vuscular volume dysregulation  Hypertension  Dyslipideamia  Anaemia and iron metabolism disorders  Protein-energy metabolism and nutritional status (huge problem)  Structural growth failure in all phases (feotal, infantile, childhood and pubertal) Management of chronic kidney disease Mineral and Bone Disorder  Hormonal and biochemical disturbance  Calcium and phosphorus  Parathyroid hormone  Fibroblast Growth Factor 23 (FGF23) early at stage 2 enhances phosphate excretion  Vitamin D metabolism  Alterations in bone metabolism  Changes in bone turn over  Mineralisation  Elongation and strength  Extra skeletal calcification Management of chronic kidney disease Goal of medical management CKD-MBD  Correction of hyper-phosphateamia (phosphate binders (Sevelamar), low phosphorus diet)  Avoiding positive calcium balance beyond what’s needed for growth  Limiting the dose of calcium based phosphate binders  Timely introduction of non-calcium based phosphate binders prevents vascular calcifications  Correction of secondary hyper-parathyroidim  Use calcitriol and vitamin D anologues to keep calcium in age appropriate range Management of chronic kidney disease Dietary management High phosphorus food items to be avoided 1. Dark coca cola/ sodas, 5. Dried beans and peas chocolate drinks and cocoa 6. Nuts and nut butters 2. Diary products (Cheese, milk, Ice cream and yogurt) 7. Chocolate 3. Organ meats and liver 8. Bran cereals, oatmeal, whole grain products 4. Oysters and sardines 9. Egg yolks Management of chronic kidney disease Metabolic acidosis of chronic Kidney Disease  Kidneys excrete hydrogen ion, reabsorb filtered bicarbonate and generate new HCO3 and other buffers  Renal ammonia genesis responsible for Hydrogen Ion regulation Renal damage  Acidosis early problem especially with tubular dysfunction  At onset normal anion gap acidosis later high anion gap Management of chronic kidney disease Consequences of metabolic acidosis  Bone acts as buffer Release of Calcium from bone High PTH Growth failure Osteopenia  Increases rate of progression of ESRF  Contributes to hyper-kaleamia  Adversely affect protein and muscle metabolism  Simulates inflammation  Enhances insulin resistance Management of chronic kidney disease Management of acidosis  Correction of acidosis seems to control the progression of CKD  Improves secondary hyperparathyroidism  Improves nutritional status  Improves muscle strength  Improves quality of life Management of chronic kidney disease Management of acidosis  Maintain serum bicarbonate at or above 22mEq/L (20 mEq for infants less than 2 years)  Add Citric acid / sodium citrate or sodium bicarbonate x 3 times a day  Monitor sodium carefully  TRC101 or Veverimer is a novel , polymer for treating metabolic acidosis Note however  Hypocalceamic patients could develop tetany with alkali therapy  Alkali therapy may promote vascular calcifications  Blood collection should be done before the first alkali dose Management of chronic kidney disease Dietary management of metabolic acidosis  Increase fruit and vegetables but take care not to induce hyper-kaleamia  Reduce Hydrogen ion intake (take away acid foods and increase base-producing foods)  Reduce animal protein Management of chronic kidney disease Potassium balance in chronic kidney disease  Inadequate renal potassium excretion due to decreased nephron mass  Decreased collecting ducts leads to decreased secretion of potassium  Hyperkaleamia is a risk factor for arrhythmias and cardiac arrest and higher mortality Management of chronic kidney disease Medications that may contribute to hyper-kaleamia  Angiotensin converting enzyme inhibitors,  Angiotensin Receptor Blockers,  Potassium sparing diuretics,  Calcineurin inhibitors  Prostaglandin inhibitors (e.g. Non-steroidal anti-inflammatory drugs)  Other conditions contributing to hyperkaleamia  High dietary potassium intake  Catabolic state,  Increased tissue break down,  Inorganic metabolic acidosis Management of chronic kidney disease Examples of high and low potassium foods Food type High potassium foods Relatively low potassium foods Fruits Orange, orange juice Apple, apple juice, blue berries, Banana, Mango, papaya grapes Pine apple and pine apple juice Vegetable Tomatoes and tomato Egg plant products Onions Potato Cucumber Pumpkin Other foods Chocolate Rice Salt substitutes Pasta Nuts and seeds Bread (not whole grain) Management of chronic kidney disease Adaptive increase in colonic potassium secretion in CKD  Potassium secretion is related to stool weight- Avoid constipation  Also avoid traumatic blood sampling and haemolysis  Also use age appropriate normative ranges, infants and young children have higher serum potassium levels Management of chronic kidney disease Treatment of hyper-kaleamia  Prevent  Rapidly decrease the risk of life threatening arrhythmia  Remove potassium from the body Prevent  Avoid certain foods  Sodium polystyrene sulfonate is a cation-exchange resin (Potassium binder)  Can be used orally or rectally (may cause colonic necrosis rarely)  Calculate based on 1mEq potassium per 1g resin  Novel agents include Patiromer and Zirconium for non-emergent hyperkaleamia Management of chronic kidney disease Treatment of hyper-kaleamia Rapidly decrease the risk of life threatening arrhythmia  Confirm high hyper-kaleamia  Note ECG abnormalities  Shift potassium intra-cellularly  Cardiac membrane stabilization Shift potassium intra-cellularly  Sodium bicarbonate administration intravenously  Insulin and glucose intravenously  Beta 2 agonist (Salbutamol via nebuliser) Cardiac membrane stabilization  Calcium gluconate intravenously Management of chronic kidney disease Treatment of hyper-kaleamia (cont) Remove potassium from the body  Loop diuretic intravenously or oral  Sodium polystyrene and other potassium binding agents  Dialysis Management of chronic kidney disease Sodium balance, Intra-vascular volume expansion and Hypertension  CKD can result in a spectrum of dysnatreamias  Sodium loss  Obstructive uropathies and / or renal dysplasia  Peritoneal dialysis patients  Chronic sodium depletion may lead to growth impairment  Sodium retention with intravascular volume expansion and hypertension  Nephrotic syndrome  Glomerulonepritidies  Severely decreased GFR  Monitor dietary sodium intake closely  Minimum sodium restriction is 1500-2400mg/day Management of chronic kidney disease Dyslipideamia in CKD  A common problem in CKD especially in children with nephrotic-range proteinuria  Risk that it contributes to morbidity especially in presence of obesity and metabolic syndrome Management of chronic kidney disease Anaemia and Iron metabolism in CKD  Well known complication of renal disease  Anaemia complicates renal disease in 50%  Erythropoietin axis is disrupted in CKD  Erythropoietin stimulating agents have revolutionised treatment  Set Haemoglobin target at 8-11g/dl Management of chronic kidney disease Anaemia and Iron metabolism in CKD Iron dysmetabolism  Iron metabolism is disrupted in CKD due to elevated Hepcidin  Hepcidin blocks Iron absorption from the gut and sequesters iron in macrophages and hepatocytes  Iron therapy stimulates Hepcidin  Growing concern for Iron overload Management of Anaemia  Transfuse as needed  Start ESA as soon as Anaemia noted  Monitor iron status  Avoid iron overload  Avoid infection and inflammation which stimulate Hepcidin Management of chronic kidney disease Protein-energy metabolism and nutritional status in CKD Nutrition impacted in many ways in CKD  Anorexia  Altered gut motility  Mal-absorption  Intestinal dysbiosis  Ureamic abnormalities of energy, protein, lipid and carbohydrate metabolism Nutritional Assessment  Dietary assessment  Anthropometric assessment  Advanced assessment of body composition  Biochemical assessment Management of chronic kidney disease Protein-energy metabolism and nutritional status in CKD Nutrition impacted in many ways in CKD  Protein restriction is not recommended in CKD  Recommended intake of protein  Daily recommended intake of protein in stage 3 is 100-140%  Daily recommended intake of protein in stage 4-5 is 100-120%  Dialysis and Nephrotic syndrome are associated with additional protein loss Management of chronic kidney disease Structural growth in CKD  Growth impairment is common in CKD  Up to 35% of children have growth impairment  Growth impairment is associated with poor outcomes  Major disturbance in GH / Insulin like growth factor (IGF-1) axis  Other factors important are  Malnutrition  Metabolic acidosis  Fluid and electrolyte dysregulation  CKD-Metabolic Bone Disease  Anaemia Treatment  Prevent  Treat with growth hormone Management of chronic kidney disease ESRD  State at renal dysfunction can no longer be sustained by medical management  Renal replacement therapy (RRT) (Dialysis or transplant) becomes necessary  Initiate RRT at stage 4 CKD Management of chronic kidney disease ESRD Indications for starting dialysis  Diuretic resistant fluid overload  Severe fluid restrictions that does not support linear growth  Uncontrolled electrolyte abnormalities  Ureamic symptoms  Initiate dialysis as GFR approaches 10-15ml/min/1.73m2 Management of chronic kidney disease ESRD Renal transplantation  Better than dialysis  Pre-emptive  After dialysis Management of chronic kidney disease Summary  CKD is a serious condition  CKD is complex and expensive condition to manage  Prevent ESRD by paying attention to simple things  Urine examination abnormalities  Proteinuria  Haematuria  Antenatal congenital urinary tract anomalies Management of chronic kidney disease The ESRD management complex Chronic Kidney Disease Transplant Dialysis Challenges of managing chronic kidney disease in children (CKD) Henry Stokes Mulenga 29.05.2023 Malaria in Children Henry Stokes Mulenga 10.10.2023 Malaria in Children Introduction  Importance of malaria  Aetiology  Life cycle  Pathogenesis of the intra-erythrocyte cycle  Clinical manifestations  Diagnosis  Cerebral malaria  Acute haemolysis  Acute kidney injury  ARDS / Multi-organ dysfunction  Treatment  Prevention Malaria in Children Importance of malaria  Nearly accounts for ½ millions deaths globally  65% of deaths are in children < 5years living in Sub-Saharan Africa  90 % of global malaria cases occur in Sub-Saharan Africa  106 countries remain at risk of malaria transmission  In 2015 there 114 million individual infections of malaria  Actually many countries are moving towards malaria elimination Malaria in Children Aetiology Infection with  P. falciparum  P. malariae  P. ovale  P. vivax  P. Knowlesi Transmission  Bite of female anopheles mosquito  Blood transfusion  Via contaminated needles  Trans-placentaly Malaria in Children Life cycle Sexual cycle (sporogony phase) in mosquitoes  Mosquito ingests gametes  Macrogamete  Exflagellating microgamete  Ookinete  Ocysts  Sporozoites Malaria in Children Life cycle Asexual (schizogony phase) in humans after infection with sporozoites  Exo-erythrocytic or hepatic phase end with release of merozoites in circulation  Infected hepatocyte with sporozoite  Sporozoites into Schizonts  Depending on species:  P. faciparum, malariae and knowlesie immediate development into merozoite and infection of RBC  Or has Schizont delayed development into hypnozoite P. vivax & ovale then merozoite Malaria in Children Life cycle Asexual (schizogony phase) in humans after infection with sporozoites (cont)  Erythrocytic phase  Develops into Ring forms  Develops further into a trophozoite  Schizont  Merozoite release and clinical disease  And Gametocyte development which are ingested by mosquito with a blood meal Malaria in Children Pathogenesis of the intra-erythrocyte cycle Infected RBCs are abnormal  Infection increases adherence vascular endothelium  Mechanical micro-vascular obstruction  Activation of immune cells and release of cytokines  Endothelial dysfunction  Vascular permeability  Dys-regulation of coagulation pathways  Some parasites seem to be predisposed to adhesion Endolithium Protein C Receptor Malaria in Children Life cycle Schizont rupture and merozoite release and fever  RBC rupture results in release of toxins Haemazoin and Glucose Phosphate Isomerase (GPI)  Stimulation macrophages  Release of cytokines  Formation of immunocomplexes  Febrile paroxysms alternating with periods fatigue otherwise well Malaria in Children Clinical manifestations Pathogenesis of the intra-erythrocyte cycle Uncomplicated Malaria  Headache  Fatigue  Myalgia  Followed by fever, chills, sweats and malaise  May progress to severe malaria Severe malaria  Cerebral malaria (coma and convulsions)  Severe anaemia  Metabolic acidosis and respiratory distress  Acute renal failure Malaria in Children Severe Malaria Adults Children Cerebral malaria Cerebral malaria, Adult Respiratory Distress Syndrome Neurologic deficit Hepatitis and Jaundice Abnormal brain reflexes Acute Renal Failure Elevated CSF pressure Mortality of Cerebral Malaria is Severe anaemia increased by : Metabolic Acidosis Acidosis Retinal vessel changes, Renal Failure papilloedema and ring haemorrhages Also may be present: ARDS Acute Renal Failure Malaria in Children Clinical manifestations Criteria for severe malaria Clinical  CNS  Impaired consciousness, prostration, convulsions  RS  Respiratory distress due to acidosis  Acute pulmonary oedema  CVS  Shock, increased capillary refill, causing cardiopulmonary arrest.  Haematological  Jaundice, severe anaemia, abnormal bleeding Malaria in Children Clinical manifestations Criteria for severe malaria Clinical (cont)  Metabolic  Lactic acidosis, Hypoglycaemia  Renal  Acute kidney injury, glomerular nephritis, nephrotic syndrome  GIT  Vomiting, abdominal pain and diarrhoea Malaria in Children Clinical manifestations Criteria for severe malaria Laboratory  Hyper-parasiteamia Age Percentage of infected RBC Less than 5 years 2 % or more 5 years or older (non- 5% or more immune) 5 years or older (semi- 10% or more immune) Malaria in Children Diagnosis Laboratory and Imaging studies Rapid diagnostic tests (mRTD)  Monoclonal antibody tests detects Plasmodium specific antigens  Plasmodium specific antigens include  P falciparum histidine rich protein 2 (HRP-2)  Pan-plasmodium parasite lactate dehydrogenase  Pan-plasmodium aldolase Malaria in Children Diagnosis Laboratory and Imaging studies Rapid diagnostic tests (mRTD) (cont)  Sensitivity may be compromised by inadequate handling and storage  Recently deletion of Pfhrp2/3 has been detected which can lead to false negative  Rapid tests are able to detect P falciparum but are unable to differentiate between P vivax, P ovale, P malariae  Sensitivity is low for non-falciparum species and in patients with low parasiteamia  Point of care test and must be followed by microscopy Malaria in Children Diagnosis Laboratory and Imaging studies Microscopy  Accurate and inexpensive test  Will determine species and estimation of parasite density  Light microscopic determination visualisation Giemsa stained thick and thin blood smears  Obtain several smears over three days following presentation  Negative smears are confirmed after 3 negative tests Malaria in Children Diagnosis Laboratory and Imaging studies Microscopy (cont)  Both thick and thin films should be examined  Thick smears have 20-40 x concentration of RBCs than on thin films  Thick smears are useful to scan many RBCs quickly  Thin smears allow for parasite identification and parasite density estimation  Microscopic detection relies on continuous electricity supply and trained microscopists  False negative results may result at low parasite density  And mixed species infection may be difficult to detect Malaria in Children Diagnosis Laboratory and Imaging studies (cont) Polymerase chain reaction  Most sensitive and specific modality  Allows for species determination even at low levels of parasite density (1-5 parasites / micro-litre of blood compared microscopy and mRDT 50-100 parasites / micro- litre of blood)  PCR is useful for detection of mutations associated with drug resistance  Some of the PCR methods in use are:  Conventional  Nested  Real time  Droplet digital  Isothermal PCR Malaria in Children Laboratory and Imaging studies Cerebral malaria MRImaging  Convulsions  Abnormal brain stem reflexes  Elevated CSF pressure and cerebral oedema  Neurologic deficits  Neurologic sequelae  Cortical blindness  Hearing loss Ophthalmologic complications  Retinal vessel changes  Papilloedema  Ring haemorrhages Malaria in Children Laboratory and Imaging studies Acute haemolysis Full blood count Liver function tests Clotting screen  Profound anaemia  Severe jaundice  Coagulation disorders Malaria in Children Laboratory and Imaging studies (cont) Acute Kidney Injury and Metabolic Acidosis Serum creatinine and BUN Blood gas analysis and lactate level Blood glucose level Monitor urine output including urinalysis and urine electrolytes  Hypo-voluemic shock  Hypo-glyceamia  Metabolic acidosis Malaria in Children Laboratory and Imaging studies (cont) ARDS / Multi-Organ Dysfunction Oxygenation saturation monitoring AND planned ventilation assistance and chest X-ray showing signs of hyperventilation. Rising creatinine and liver enzyme levels Abnormal chest x-ray Abnormal blood pressure and ECG  Respiratory distress / failure  Pulmonary oedema  Arrhythmia and cardiac failure Malaria in Children Henry Stokes Mulenga 11.10.2023 Malaria in Children Treatment The goals (WHO guidelines were published in March 2023) Goal with 2015 as Milestone 2020 Milestone 2025 Target 2030 comparator Reduce global At least 40% At least 75% At least 90% mortality Reduce malaria At least 40% At least 75% At least 90% incidence Eliminate malaria At least 10 countries At least 20 At least 30 from which malaria countries countries was transmitted Prevent re- Re-establishment Re-establishment Re-establishment establishment in Prevented Prevented Prevented malaria free countries Malaria in Children Global technical Strategy for malaria Eliminate malaria Transform Ensure access malaria to Prevention, surveillance Diagnosis and into key health treatment intervention Malaria in Children Treatment Strategy depends on  Disease severity ( uncomplicated vs severe)  The infecting species (P falciparum, P vivax etc)  Likelihood of resistance  Patient factors eg whether patient is able to tolerate oral medication Uncomplicated malaria: Oral Artemisinin Combination Therapy (ACT)  Patient has symptoms consistent with malaria  Patient has positive parasitological test (Microscopy or / and mRTD)  Use ACT and full course Malaria in Children Treatment Uncomplicated malaria: Oral Artemisinin Combination Therapy (ACT) Antipyretics  Use acetaminophen 15mg / kg every 4 hours  NSIA Ibuprofen is no longer recommended Anti-emetics  If a patient is still vomiting after stabilisation use parenteral Artesunate Convulsions  Patients who have more than 2 seizures in 24 hours ( consider meningoencephalitis) should be treated as severe malaria  If seizures occur, treat seizures as per guidelines starting with IV benzodiazepines.  Unless necessary avoid rectal diazepam and im paraldehyde Malaria in Children Treatment Uncomplicated malaria: Oral Artemisinin Combination Therapy (ACT)  Artemether- Lumefantrine (AL)  Ar