Week 9 Flashcards
HTLV-1 Spastic paraparesis causes in Peru
Infectious: syphilis, HIV (vacuolar myelopathy), TB, neurobrucellosis, HTLV-1. Non-infections: MS, familial spastic paraplegia, Konzo/lathyrism (failure to prepare cava appropriately), primary lateral sclerosis, trauma, B12 deficiency, anterior spinal thrombosis)
HTLV-1 Epidemiology
Worldwide prevalence 5-10 million carriers globally. 5-10 million carriers globally. Asymptomatic in majority (>95).
HTLV-1 Transmission
Parenteral (transfusion of cells, IVDU, solid organ transplant - high risk for HAM, prevented by screening in blood banks and organ donors), vertical & breastfeeding (rare before and during childbirth - screening/no breastfeeding if secure alternatives in place), sexual (only prevention). No proven treatment, no vaccine
HTLV-1 HAM/TSP
HTLV-1-assocated myelopathy (HAM)/Tropical spastic paraparesis (TSP); RF: women>men, aged 40-50y, genetic predisposition, high HTLV-1 provirus load. High HTLV1 Ab titres. Geographic variation ~0.25% Japan, 3% elsewhere. Discrepancy striking motor symptoms > mild sensory disturbance. Lumbar pain, bladder disorders, repeated falls due to ‘clumsy legs’ are early signs. Chronic inflammation of white and grey matter of lower thoracic spinal cord (infiltration of T cells - bystander effect/auto-antibodies followed by atrophy). Symptom progression variable phenotype of onset. Treatment limited evidence. 1g IV methylpred (3d) for symptom relief (screen Strongy, TB etc first. No role for antiviral therapy or interferon alpha. Symptomatic support: antispasmodics, laxatives, physio, secondary infections. Mortality ratio 2.25% vs main population (longevity affected).
HTLV-1 Adult systemic complications of HTLV-1
Effects of inflammation of the spinal cord (low back pain, constipation, unstable bladder, weakness). HTLV-1 associated uveitis, thyroiditis, calcium disorders, bronchiectasis, interstitial pneumonitis, eczema, seborrhoeic dermatitis, polymyositis, arthropathy, Sjogrens
HTLV-1 Infective dermatitis
Chronic relapsing erythematous lesions. Age 3-15y. Lesions of the scalp, ears, retroauricular areas, paranasal and perioral areas, neck, axillae, thorax, abdomen, groin and other sites. Lesions may be erythematous/scaly, exudative and/or crusted. Chronic, relapsing condition, prompt response to therapy, but recurrence upon discontinuation of antibiotics. Lymphadenopathy. Failure to thrive. Treatment: long-term antibiotic therapy (SXT), mild local corticosteroids for severe cases, follow up
HTLV-1 Adult T-cell leukaemia/lymphoma
HTLV-1 is a highly oncogenic virus. Median age 56y, long latency period 20-50y after HTLV1 infection. Aggressive proliferation of mature activated CD4+ CD 25+ T cells. Clinical presentation (lymphadenopathies, hepatosplenomegaly, visceral lesions), Diagnosis (‘flower cell’ on peripheral blood film = acute ATL patient-leukaemic cells with multilobulated nuclei), Complications (paraneoplastic hypercalcaemia, and opportunistic infections eg TB, strongyloidiasis)
HTLV-1 Associated infections
Crusted scabies. Strongyloidiasis - mortality 15-87%, hyperinfection risk (recurrent Gram negative sepsis, associated with normal eosinophils), associated with (larva currens, nephrotic syndrome, ARDS, chronic diarrhoea, small bowel obstruction), diagnosis (direct examination, serology), treatment: ivermectin
HTLV-1 Summary
RNA retrovirus, spread by cell-to-cell contact. 5-10 million carriers globally. Geographic foci: Japan, Latin America, Caribbean, Africa, Central Australia. Transmission: vertical, horizontal, blood products. 95% of carriers remain asymptomatic lifelong. HTLV1-associated myelopathy (HAM) or tropical spastic paraparesis. May be rapid or slow progression. Highly oncogenic virus-causing adult T-cell lymphoma/leukaemia (ATL). Systemic complications: infective dermatitis, strongyloides infection, autoimmune infections. Diagnosis: serology EIA/Western blot, Proviral PCR. Prevention: No vaccine, avoid infected bodily fluid transmission. Treatment: no proven antiviral treatment.
Anaemia Definition
A pathological condition in which the number of RBC or the Hb within them is reduced in number and unable to meet the body’s physiological oxygen-carrying needs (WHO). Anaemia is NOT a diagnosis, but a presentation of an underlying condition. WHO defines anaemia as Hb<12 in women, <13 in men
Anaemia Why is it important?
Symptomatic anaemia (reduction in cognitive function, exercise tolerance, capacity for work) Risk in children of (poor motor development, reduced cognitive function, behavioural disturbances). In pregnancy (risk of poor maternal and birth outcomes eg premature birth, low birth weight. Increased risk of maternal mortality and post-partum haemorrhage)
Anaemia Epidemiology
Burden of anaemia is maximal in sub-Saharan Africa and South Asia. At least 40% globally is secondary to iron deficiency - important as it is treatable.
Anaemia Challenges in resource-limited
Lack of/expensive investigations (haematinics [B12/folate/Fe], haemoglobinopathy diagnostics, haemolysis diagnostics [reticulocytes, LDH, haptoglobin, Coombs test], bone marrow biopsies, sometimes even FBCs). Potentially unreliable quality of lab tests (lack of quality assurance programmes)
Anaemia Pragmatic approach
Classify the anaemia (microcytic, normocytic, macrocytic - combination can cause normalisation). Think about common causes first (iron/haematinic deficiencies [consider trial of treatment], haemoglobinopathies/haemolysis, chronic disease, infections/infestations, bleeding - take a good bleeding history, including through menstrual history. Haematological cancers are much less common than all of the above - assess for other cytopenias/features of haematological disease). Blood films are really helpful, but need to be done before transfusion
Iron deficiency Assessment
Investigate and treat the underlying cause (why is the iron level low? Is there bleeding? Is there poor dietary intake? Pregnancy? Helminth infection? Chronic infection?) Assess severity of anaemia (determines treatment approach).
Iron deficiency Management options
Life-threatening/severe anaemia with haemodynamic compromise (transfuse RBC/whole blood, manage any bleeding, once patient stable, likely to need additional iron supplementation). Non-severe anaemia (oral iron supplementation, IV iron supplementation if available [helpful if surgery planned within a few weeks, lack of response to oral, malabsorption, dialysis-dependent renal disease], treat for 6 months (and min 3/12 post normalisation of FBC)
Iron deficiency When to transfuse in iron deficiency
Severe symptomatic anaemia. Transfusion has clear risks and complications. Transfuse the minimum amount of blood necessary to improve the clinical condition. Short term fix -> always aim to correct the underlying cause. Always weigh up risks vs benefits
Iron deficiency Accelerating anaemia reduction
Contributing sectors (health & nutrition, food & agriculture, water, sanitation & hygiene, education, social protection, labor, trade & industry, finance). Action areas (analyse data on causes and risk factors. Prioritise key preventive and therapeutic interventions. Optimise serve delivery across platforms and sectors. Strengthen leadership, coordination, and governance at all levels. Expand research, learning and innovation). Improve sustained, equitable and effective coverage of priority interventions for anaemia prevention, diagnosis, and treatment. Tackling the direct cause of anaemia (1 Improved micronutrient status, 2 reduced infection, inflammation, and chronic diseases, 3 reduced gynaecological and obstetric conditions (eg abnormal uterine bleeding), 4 Improved screening and management of inherited red blood cell disorders) -> optimise haemoglobin synthesis, prevent excessive destruction of red blood cells and decrease blood loss -> 2025 World Health Assembly Target 2 (achieve a 50% reduction of anaemia in women of reproductive age) -> 2030 sustainable development goals (Zero hunger (SDG2) and good health and wellbeing (SDG3), and SDG 2.2 end all forms of malnutrition)
Iron deficiency Summary
Globally anaemia is extremely common and is considered by the WHO as a serious global public health problem. Iron deficiency is by far the commonest cause. Always try to investigate and treat the underlying cause of anaemia (and the underlying cause of iron deficiency). Simple diagnostics (eg blood films) can be very helpful
Blood transfusion Epidemiology
Lack of blood contributes to 25% maternal deaths. Haemorrhage cause 10-40% of trauma deaths. Inequitable access - LMIC blood donations 5 per 1000 population per year (vs 33 per 1000 in HIC). Key points: is the transfusion definitely necessary? Is there an alternative to transfusion? Blood transfusion services are challenging and expensive - research capacity building and creating local solutions is essential.
Blood transfusion Service
Requirements (collection, processing, storage, governance), Challenges (complex and expensive, family/replacement donors, anaemia/infection prevalence, financial, socio-cultural), and Solutions (capacity building, local solutions, awareness, community centredness, regular donation schemes)
Blood transfusion Zipline
Use of drones for delivery of blood products in Rwanda -> faster delivery times, -> less blood component wastage
Blood transfusion Alternatives
Medical (haematinic replacement, antifibrinolytics eg tranexamic acid, erythrocyte stimulating agents eg erythropoietin), Surgical (cell salvage, surgical techniques to minimise blood loss)
VTE Epidemiology
VTE is estimated to cause at least 3 million deaths a year worldwide. VTE causes >40,000 deaths in Europe every year. An estimated 300,000 VTE-related deaths occur in the US each year.
VTE Why treat?
If DVT remains untreated, 15-24% of these patients will develop pulmonary embolism (PE). PE during pregnancy may be fatal in almost 15% of patients, and in 66% of these, death will occur within 30 minutes of the embolic event
VTE Dilemmas with management in pregnancy
Anticoagulation (can prevent potentially fatal PE, increases risk of bleeding - especially around time of delivery), LMWH (safest but expensive), UFH (can be used in pregnancy but needs some APTT monitoring and risk of heparin-induced thrombocytopaenia and thrombosis (HITT) and osteoporosis), Warfarin (teratogenic in T1, increased risk of fetal bleeding throughout pregnancy, needs stopping at least 2/52 prior to delivery as crosses placenta -> unacceptable bleeding risk for fetus during delivery) Not enough evidence yet to recommend direct oral anticoagulants (DOACS - Rivaroxaban shows fetal toxicity in animal studies, apixaban does not)
VTE Summary
VTE is common but the management remains very difficult in low-income settings. Management is especially difficult in pregnancy. Pragmatic decision making is often required.
Haematology Summary
Anaemia is a serious public health problem requiring a multi-sectorial approach. Blood transfusion services are challenging and expensive (research capacity building and creating local solutions is essential, always think about alternatives to transfusion). Partnerships can provide a useful means for approaching resource shortages.
PaedOnc Public health advocate
Are you a floor mopper or a tap turn offer
PaedOnc Functioning cancer service
Needs referral patterns, supply lines, skilled physicians, skilled nurses, surgical services, laboratory (pathology, haematology, blood transfusion, microbiology, biochemistry), radiology, radiotherapy, palliative care, prevention
PaedOnc Approach
There are two solutions to every problem - the one for now, and the one for the future. Need to look after the patient in front of you, whilst planning for the long-term sustainable option.
PaedOnc Virtual tool kit
Clinical protocols and SOBs, chemotherapy guidelines (procurement, storage, distribution, reconstitution), chemotherapy automated prescribing, network database, pocket guides for nurse/doctors/pharmacists, play-therapy manuals and tools, parents handbook, NGO guidelines, early warning signs awareness campaigns, outreach and national network management guide. Childhood cancer survivors
PaedOnc Acute lymphoblastic leukaemia (ALL)
Leukopaenia (neutropaenia, fever, infections), Thrombocytopaenia (bruising, bleeding), Anaemia (pallor, fatigue, weakness, shortness of breath), Leukocytosis (bone pain, stroke, cranial nerve palsy, renal failure), extra-medullary sites (generalised lymphadenopathy, hepatosplenomegaly), B-symptoms (weight loss, drenching night sweats, unexplained fever, bone pain)
PaedOnc Non-Hodgkin lymphoma
Rapidly growing. Most common between age 5-15, almost never <3y. Symptoms usually rapid in onset <3m. Rapidly growing mass most commonly affecting (jaw, retro-orbital LNs, mediastinum, abdomen - liver, LNs, spleen, kidney), B symptoms (night sweats, bone pain, weight loss, unexplained fever), CNS/PNS signs (central nerve palsy, lower limb weakness, constipation, incontinence - urine/stool) Signs of bone marrow failure (anaemia, neutropaenia, leucopaenia)
PaedOnc Hodgkin
Slow growing mass. Swollen LN (groin, neck, chest, armpit), hepatosplenomegaly, B symptoms (night sweats, bone pain, weight loss, unexplained fever), recurrent infections
PaedOnc Retinoblastoma
Symptoms involving one eye or both include: leucocoria (white pupil that does not reflect the light), strabismus (eye to become crossed because of loss of vision), painful red eye, decreased vision in one eye, eye swelling or proptosis. Most common in infants and young children. (Almost all diagnoses before age six years)
PaedOnc Wilm’s tumour
Symptoms/signs include: child is generally well, abdominal mass +/- pain, haematuria, urinary tract infection, hypertension
PaedOnc Brain and spinal cord tumours
Children who present with a short history and obvious symptoms are likely to have aggressive disease in comparison with those who have a long history of subtle symptoms. Symptoms include: persistent headache, new onset seizures, raised ICP signs/symptoms (headache and vomiting on waking or early morning), visual disturbances, cranial nerve abnormalities, gait abnormalities (eg ataxia), changes in continence, deteriorating school performance or developmental milestones, behaviour changes - lethargy, aggression
Blood film Atypical lymphocytes
Larger lymphocytes with darker cytoplasm
Blood film Blasts
Usually large, high nuclear-cytoplasmic ratio. Scanty cytoplasm (+/- granules or Auer rods), Immature chromatin (fine, open - rather than mature cells which have clumped nuclear material), prominent nucleoli
Blood film Useful tool
buku medicine - valuable tool
Blood film Case 1
Anaemia, hypersegmented neutrophil, schistocytes, tear drop, anisopoikilocytosis. Diagnosis: severe B12 deficiency (macrocytic anaemia with hypersegmented neutrophils - fragments in severe cases)
Blood film Case 2
Bite cells (degmacytes), polychromasia. Diagnosis: G6PD deficiency
Blood film Case 3
Thrombocytopaenia. Diagnosis: ITP (
Blood film Case 4
Hypochromic anaemia, anisopoikilocytosis (different shapes and sizes), microcytic anaemia, target cells. Diagnosis: Iron deficiency anaemia
Blood film Case 5
Sickle cells, polychromasia
Blood film Case 6
Normal blood film
Blood film Case 7
mature lymphocytosis, smear cells. Diagnosis: CLL
Blood film Case 8
promyelocyte, promyelocyte, metamyelocyte, neutrophil precursors, myelocytes. Diagnosis: CML
Blood film Case 9
vacuoles within cytoplasm. Diagnosis: Burkitt lymphoma
Blood film Case 10
Blast cells, smear cells. Diagnosis: AML
Blood film B12 deficiency
All ages: infection (H pylori, giardia, tapeworm), malabsorption (pernicious anaemia), comorbidities (gastric resection/banding, coeliac, tropical sprue, Crohn’s). Infants (congenital - transcobalamin deficiency, Imerslud Gasbeck Syndrome), Pregnancy (due to higher requirements), Older (malabsorption - achlorhydria secondary to PPI or atrophic gastritis)
Blood film G6PD deficiency
X-linked, female carriers have increased resistance to malaria. Variable phenotype (Mild in African, Moderate in Asian, Severe in Mediterranean patients). Pathophysiology: G6Pd reduces nicotinamide adenine dinucleotide phosphate (NADP) to NADPH. This is the only source of NADPH for the red cell. NADPH is needed to reduce glutathione. Reduced glutathione clears free oxidants -> deficiency results in increased susceptibility to oxidative stress. Clinical features: Neonatal jaundice (peaks at 2-3d after birth, variable severity), Acute haemolysis (triggered by ‘oxidant’ drugs/food/infections), Chronic non-spherocytic haemolytic anaemia (CNSHA)
Blood film ITP
Primary ITP: acquired immune-mediated disorder characterised by a platelet count <100 and absence of any obvious initiating or underlying disorder. It can be newly diagnosed, persistent (2-12 months), chronic (>12 months). Treatment: 1st line steroids, IVIg, anti-D. 2nd line rituximab, splenectomy, TPO agonists, steroid-sparing immunosuppressants
Blood film Sickle cell disease
~15,000 people with SCD in UK (~9% on long-term transfusion programme). ~300 infants born with SCD in UK each year. Caused by inheritance of the sickle mutation on the HBB gene (Glu6Val, bs). Sickle cell trait = HbAS, Sickle cell anaemia = HbSS, Sickle cell disease = HbSS or sickling compound heterozygotes = HbSC, HbS/b0, HbS/b+, HbSC, HbSOArab. In West Africa, SCD responsible for 16% of all deaths <5 year olds. In Jamaica, 10% of SCD infants die between 6-12 months of age. In the UK, 99% survival to age of 16 years. Pathophysiology: In hypoxic states, erythrocytes become rapidly, but reversibly, deformed. Intracellular polymerisation of the abnormal HbS molecule stretches cell into rigid sickle form. Sickled cells cause vaso-occlusion, along with many other cellular and plasma factor interactions -> cycle of repeated ischaemia and inflammation. Re-oxygenation restores the normal red cell shape. Cells cycle in and out of this state until forced into intravascular haemolysis or extravascular removal by the reticuloendothelial system. HbS is a low oxygen affinity haemoglobin -> right shift on the oxygen dissociation curve -> partly explains the chronic anaemia in SCD (which is not all due to haemolysis)
Blood film Chronic lymphocytic leukaemia
Incidence 4.2 per 100,000 per year. Median age of presentation 72, Men>women. Caucasian > other ethnic groups. >80% incidental diagnosis. Diagnosis >5x10^9/L circulating clonal B cells persisting for >3 months and of characteristic immunophenotype
Blood film Chronic myeloid leukaemia
Pathophysiology: part of ABL from 9 moves to the BCR on 22 (and part of 22 moves to 9). Philadelphia (Ph) chromosome = abnormal 22 that carries the BCR-ABL 1 fusion gene. BCR-ABL 1 fusion gene codes for a protein with excess tyrosine kinase activity. Ph chromosome is an acquired abnormality of a haemopoietic stem cell and so found in cells of both myeloid and lymphoid lineages. Clinical presentation: median age at diagnosis = 57 years. 20% of patients >70 years, <5% of patients <18. 50% diagnosed on incidental FBC finding. B symptoms, splenomegaly, symptoms of anaemia/thrombocytopaenia. Blast phase vs chronic phase. Treatment: tyrosine kinase inhibitor
Blood film Burkitt lymphoma
Aggressive B-cell non-Hodgkin’s lymphoma, uniformly associated with MYC translocations. Doubling time of 25 hours - probably fastest growing of any cancer. WHO-HAEMS Classification: EBV positive vs EBV negative - this replaces previous classification of endemic/sporadic/immunodeficient. Endemic (African) BL - uniformly EBV positive, 3-6 cases per 100,000 children per year in equatorial Africa. Incidence is increasing in line with increasing HIV and malaria. Classically presents with jaw or facial bone tumours. Sporadic BL - 2-3 cases per million per year in Europe. 30% of paediatric lymphomas, 1% of adult NHL, Men>women (4:1). Immunodeficiency-associated BL - essentially HIV, occurs independently of CD4 count and so incidence has not fallen with introduction of HAART.
Blood film Acute myeloid leukaemia
Medan age 70y. Age <65: 3-8 cases per 100,000 adults per year, 40% 5-year survival. >65y 0.17 cases per 100,000 adults per year, 10% 5 year survival. Adults 18-60y induction therapy achieves clinical remission in 60-80% of adults, allograft in first clinical remission offers significant overall survival benefit. Allograft long-term survival for adverse AML is 30% (but chemo alone is much worse)
Yellow fever Historical perspective
First cases described in Hisponalia (Domenican Republic) 1495 - first epidemic described in Guadeloupe in 1647. Feared disease at the turn of the 19th Century - Western Hemisphere and the coastal regions of West Africa (Ships ‘Yellow Jack’ flag. Now commonly believed YFV originated in Africa, taken to the Americas on ships carrying anopheles eggs.
Yellow fever Virology
Flavivirus, enveloped virus, ssRNA, surface proteins are important for infecting cells (E dimer used for cell surface attachment) - pantropic virus (affects many cells), predilection for the liver also. Internalised by endocytosis, replication cycle starts in endothelial reticulum and finishes in the golgi apparatus. pH dependent phenomenon. Genotypes 1 & 2 West Africa, 3, 4, 5 East/central Africa. 6 & 7 South America
Yellow fever HCQ
HCQ increases the pH within the cell, but is not able to get inside cells at levels required to increase the pH so does not work for any viral infection
Yellow fever Epidemiology
Global distribution: Tropical belt of Africa and South America (around rainforests).
Yellow fever Why not SE Asia etc?
Vector is Aedes aegypti and A albopictus have the potential to carry YF - these go around the globe - why isn’t there any YF in SE Asia or Pacific region? Noone really knows, but a number of theories. 1 Absence of centuries of slave trade with Africa. 2 Less competent vectors? 3 Relatively low viral loads of handful of imported cases - care in urban centres, less likelihood of establishment of sylvatic cycle. 4 Cross-protective immunity between flaviviruses?
Yellow fever Transmission
1 Sylvatic (jungle) cycle - this is the maintenance cycle, 2 Anthropogenic sylvatic cycle (humans go into forest, get infected, and then take it back to the urban or village environment), 3 Village epidemic 4 Urban epidemic (this is the most feared, where mosquitoes are able to thrive and many non-immune get massive epidemics). 1-4 in Africa, 1 and 4 only in South America
Yellow fever Clinical disease
Short incubation period 3-6d (may be longer <21d). Asymptomatic or mild febrile illness in many cases. Some progress to ‘toxic’ phase of infection (0.8-7.5% will progress to this stage and often come to the attention of medical facilities - 30-60% CFR)
Yellow fever Viraemic phase
d3-6 Clinical features: headache, myalgia, lumbosacral pain, nausea, malaise, prostration, dizziness, conjunctival infection, furred tongue, red at tip, Bradycardia (Faget’s sign). Lab features: leukopaenia, neutropaenia, AST»ALT, proteinuria. Then immune response to E protein, neutralising - symptoms abate for 2-24h
Yellow fever Severe disease
d7-12 ‘period of intoxication’ CFR 30-60% antibody-complex mediated disease. Clinical features: headache, epigastric pain, vomiting, prostration, malaise, jaundice, olig/anuria, tender liver, hypotension -> shock, stupor -> coma, haemorrhage, convulsions, hypothermia, Lab: leukocytosis, AST>ALT, proteinuria, hypoglycaemia, acidosis.
Yellow fever Predictors of mortality
Older age >45y, neutropaenia, AST >3500, hyperbilirubinaemia, high YFV RNA levels, renal dysfunction
Yellow fever Should a liver transplant occur
No reported outcomes from liver transplantation in severe yellow fever. UK do not have a cohort of immunised surgeons. YF virus known to infect many organs, death often rapid and multifactorial., Virus remained detectable by PCR, therefore risk of graft infection
Yellow fever Antiviral treatment
No effective antiviral therapy established. Unclear if effective antiviral therapy could alter disease course of established toxaemic phase. Ribavirin (activity in vitro and small animal models at high doses, no benefit in several non-human primate models. The doses required to have any intracellular effect are likely to be toxic). Sofosbuvir (relatively weak activity in vitro, some protection in small animal model when administered prior to yellow fever virus challenge).
Yellow fever Vaccine
Max Theiler - Nobel Prize in Physiology or Medicine “for discoveries concerning yellow fever and how to combat it” - the only time Nobel has been awarded for a vaccine. YF-Vaccine (17D). Live attenuated YFV. Has no ability to infect vectors - low level replication in humans (important when given in areas where vectors are available but no YF). >90% protection after 10d, >99% protection after 30d, single-dose probably provides life-long protection. Requirement of a cold-chain. Many countries (national vaccination programme, many others a requirement for travel/entry)
Yellow fever Contraindications to vaccination
Absolute CI: under six months old, confirmed anaphylactic reaction to. A previous dose or any components of vaccine, or egg, those who have a history of thymus disorder and thymectomy following a thymus disorder. Patients with primary or acquired immunodeficiency due to a congenital condition, disease process, or treatment.
Yellow fever Galidesivir
Small molecule antiviral, nucleoside (adenosine) analogue. Broad-spectrum activity in vitro against RNA viruses - blocks viral polymerase similar to sofosbuvir but only IV. Survival benefits in animal models of Ebola, Marburg, Zika, Yellow fever. Survival benefit in Syrian golden hamster model of YF - when treatment initiation 4d after lethal challenge
Yellow fever Summary
Yellow fever remains a large burden disease. High morbidity/mortality in subsets (no decent data on the predictors of morbidity and mortality at the onset of the illness). 17D vaccine highly effective (know your contraindications, for travelers (especially short travel) consider risk vs benefit). No licensed therapy (sofosbuvir and galidesivir heading into clinical trials)
Bartonella Summary
Bartonella spp are Gram-negative, facultative intracellular pathogens, emerging and reemerging human diseases. Associated with a range of human and animal infections. Emerging zoonotic pathogen and affects humans, domestic animals and wildlife. Bartenellosis is characterised by a prolonged intraerythrocytic bacteraemia within a diverse array of reservoir hosts. The severity of the clinical manifestations is often correlated with the immune status of the patient (other factors: the species infecting the host, virulence factors, and bacterial load)
Bartonella Pathogenesis
Bartonella invades endothelial cells and erythrocytes. Induces angiogenesis via VEGF and other growth factors. Avoids immune clearance by intracellular localisation. Chronic infection through persistent bacteraemia. Subversion of immune system: inhibition of apoptosis in host cells. Bacterial virulence factors.
Bartonella Progression phases
Adhesion (infection of the primary niche in mammalian reservoir host, infection waves seeded from the primary niche, antibody response that limits the bacteraemia), Invasion, Replication, Persistence
Bartonella Clinical manifestations
Neuropathy (varied), aneurysm, bacillary peliosis (hepatic), epithelioid haemangioendothelioma, arthritis, Verruga peruana (Peruvian warts), endocarditis, myocarditis, vasoproliferative and lymphatic tumours, bacillary angiomatosis, vasculitis/thrombosis
Bartonella Vectors
Lutzomyia verrucarum sandfly = B bacilliformis, Cat = B henselae, B clarridgiae, Human body louse = B quintana, Rat = B elizabethae, Vole = B vinsonii
Bartonella Syndromes
Carrion disease = B bacilliformis, Cat scratch disease = B henselae, B clarridgiae, Trench fever = B quintana, Bacteraemia/endocarditis = B henselae, B elizabethae, B vinsonii, B quintana, Bacillary angiomatosis = B henselae, B quintana, Peliosis hepatis = B henselae, B quintana
Bartonella B henselae
Primary cause of cat scratch disease. Associated diseases: bacillary angiomatosis (in immunocompromised host), Parinaud’s oculoglandular syndrome (granuloma in eye). Transmission via scratches or bites from infected cats (fleas play a role in cat infection cycles). Clinical presentation: immunocompetent - cat scratch disease (regional LN, fever, fatigue and headache), immunosuppressed - bacillary angiomatosis (affected patients present with vascular lesions that most frequently involve the skin but can affect other organs, such as bone and LN, can be life-threatening if untreated, mimic Kaposi sarcoma in HIV). Diagnosis: Clinical history and exposure to cats. Lab: Serology for B henselae, PCR, Biopsy for angiomatous lesions (Warthin Starry stain). Treatment: LN Azithromycin 5d (or Clari, Rif, SXT), Bacillary angiomatosis: Erythromycin or doxycycline 12w minimum - if response not satisfactory, duration can be extended (optimal duration not determined, but longer with invasive disease)
Bartonella B quintana
Trench fever (also can cause bacillary angiomatosis, endocarditis). Associated with homelessness and poor hygiene (transmission: Pediculus humanus corporis - human body louse, no known animal reservoir). Worldwide distribution (sporadically reported in US, EU, Russia, Brazil, and East Africa). Outbreaks reported in homeless, refugees and prisoners (HIV, EtOH, IVDU higher risk). Seroprevalence studies of homeless population in USA and France found 8-53% had B quintana infection compared with 0-2% of healthy blood donors. Incubation 5-20d. Clinical: Trench fever (cyclical fever every 5-6d, severe headache, bone pain (esp shins), relapsing, chronic form in some cases), Immunocompromised: Bacillary angiomatosis (vascular lesions affecting skin and internal organs - occurs in patients with advanced HIV CD4<100, Bq more likely to have lytic bone lesions), Culture negative endocarditis (20-43% of patients with B quintana have endocarditis, causes up to 15% of CNE Bq>Bh causing endocarditis), Chronic infection can persist asymptomatically or with mild nonspecific symptoms. Bacillary peliosis hepatitis (occurs in patients with HIV CD4<100, present with abdo pain, hepatosplenomegaly with or without systemic symptoms, elevated ALP) Lab: BC (difficult due to fastidious growth), Serology (IgM/G), PCR, histopathology for vascular lesions. Treatment: Doxycycline 28d + Rif 14d. Bacillary angiomatosis and endocarditis need prolonged doxy or erythro with gent in severe cases - treatment of BA depends on the presence of bacteraemia and severity of illness
Bartonella B bacilliformis
Carrion’s disease, Oroya’s fever two phases: acute and chronic. Geographically confined to Andean region (mostly Peru). Transmission: vector-borne Lutzomyia verrucarum sandfly but not clear. Pathogenesis: infects erythrocytes and endothelial cells, physical damage and introduction of antigens into the erythrocyte membrane, producing intense erythrophagocytosis -> haemolytic anaemia. Virulence factors (adhesin, flagellin, hemi) evade the host immune response. Acute phase: increased IL-10 secretion by RBC, decrease cytokine production -> suppresses T helper cells, macrophages, and dendritic cells (favours persistent B bacilliformis infection and increase the risk of secondary infection)
Bartonella B bacilliformis acute phase
Characterised by fever and haemolytic anaemia and has a reported mortality of 44-88% untreated (acute bacteraemia for 60d) Complications are common and include super-infections such as Salmonella spp (also Toxoplasma, Histoplasma, and others). Other complications are haematological, gastrointestinal, cardiovascular and neurological. Young children are the most affected in endemic communities (presumptive protective immunity that develops with repeated infection means adults are more protected). High mortality without antibiotic therapy. RF: >45y, history of alcohol use, shock, pulmonary oedema, pericarditis, seizures, coma, anasarca, petechiae, and altered mental status. Complications: more common cardiovascular (heart failure, pericardia effusion, pulmonary oedema etc) also coagulation disorders (requires ICU))
Bartonella Oroya fever differential diagnosis
Malaria, dengue, typhoid, viral hepatitis, leptospirosis, brucellosis, Zika, Chikungunya, TB, haem malignancy, Parvovirus B19, haemolytic anaemia, aplastic anaemia
Bartonella Verruga peruana differential diagnosis
Bacillary angiomatosis, yaws, pyogenic granuloma, angioma, cutaneous lymphoma, capillary malformation, Kaposi sarcoma, NTM, leprosy, lymphomatoid papillomatosis, fibrosarcoma, reticuloendotheliosis, Molluscum contagiosum, Chickenpox, Spitz naevaus, cutaneous TB
Bartonella B bacilliformis chronic phase
May occur weeks to months after the acute illness (and there may or may not be a history of antecedent illness). Characterised by the eruption of miliar, mular or nodular skin lesions, or verrugas (‘warts’), containing serosanguinous fluid which exudes on contact. Blood-filled nodular haemangiomas of the skin - Peruvian warts (bacterial invasion of capillary endothelium and generates bacteria-filled vacuoles and localised cellular proliferation, leading to formation of warts). Warts are cutaneous, usually on the head and extremities (can persist for several weeks to months). Lesions are classified as miliary (multiple red papules <3mm), mular (blood-filled nodules), diffuse (groups of subdermal nodules >5mm). Chronic phase is a more common manifestation of inhabitants of endemic regions. Seropositive people who are asymptomatic or in chronic phase can have blood culture positive for B bacilliformis (hypothesis - this population can serve as reservoir). Younger age, higher incidence/severity/recurrent infection/chronic phase (hypothesis - humoral immunity, as a result of recurring or chronic infections, confers partial immunological protection).
Bartonella B bacilliformis diagnostics
Acute phase: blood smears (cheapest, most used but low sensitivity), culture (>70% are positive, but it takes a long time (>14d) and is logistically complicated), PCR (expensive and not available in rural areas), Immunological tests sens and spec (but can reflect persistent humoral immune response, the indirect fluorescence antibody (IFA) test, immunoblot-based protocol). An ELISA using two different antigen combinations porin B plus autotransporter E - combination is sufficient to detect anti-B bacilliformis IgG Ab. Chronic phase: clinical diagnosis with or without skin biopsy - overlap with cutaneous leishmania. Culture BC positive 13-47% (however can be asymptomatic or transient)
Bartonella B bacilliformis treatment
All evidence of poor quality. Acute phase: Cipro, CRO (severe cases in children and pregnant women), Amox/Clav (uncomplicated cases). Chronic phase: Azithromycin, Rif (some reports showed failure), Cipro. All are expert opinion (no RCT). But ciprofloxacin resistance is being described.
Sickle cell Public Health disorder
Pathophysiology (single gene disorder, different levels of severity, common symptoms, pain, infection, anaemia), Epidemiology (common genetic disorder, annual SCD births 300,000, high morbidity and mortality in Africa). Interventions (Interventions reduce childhood mortality by 70%, disease modifying medicines, curative interventions)
Sickle cell Global epidemiology
Disproportionately affects Africa >5.7m and South Asia >1.3m, with cases in Middle East >620,000 and Jamaica 57,000
Sickle cell Pathogenesis
HbS polymerisation -> sickling and haemolysis. Sickling -> vasoocclusion (impaired rheology, adhesion between sickled erythrocytes, neutrophils, endothelium and plt -> ischaemia-reperfusion injury -> sterile inflammation -> vasoocclusion (feed forward). Haemolysis -> endothelial damage -> oxidation -> abnormal heme -> sterile inflammation -> vaso-occlusion
Sickle cell Genotypes
Severe: HbSS (the most common form of sickle cell disease, also called sickle cell anaemia, HbSbetao thalassaemia (Most prevalent in the eastern Mediterranean region and India (also includes severe beta+ with <5% HbA present), HbSDpunjab (predominant in northern India but occurs worldwide), Moderate HbSC (25-30% of cases of SCD in populations of African origin), Hbsbeta+ thalassaemia (Most cases found in the eastern Mediterranean region (6-15% HbA present), Mild: HbSbeta++ thalassaemia (Mostly in populations in Africa (16-30% HbA present)) Very mild sickle cell disease HbS/HPFH (Group of disorders caused by large deletions of the beta-globin gene. Typically >30% HbF)
Sickle cell Diagnosis
Blood film with sickled cells. Sickle solubility test. Hb electrophoresis (alkaline pH), high performance liquid chromatography
Sickle cell Types and trait
Sickle cell disease: SS sickle cell anaemia, SC, SD-, Sbeta+, Sbeta0, mild disease - S-HPFH. Sickle cell trait: heterozygous state for HbS (HbAS), no serious clinical consequences, sudden death during intensive training. Haematuria, isotheuria (renal papillary necrosis) protection vs malaria
Sickle cell Clinical features
Acute: Acute pain episodes, acute anaemia, acute chest syndrome, infection inc sepsis, meningitis, stroke, priapism, aplastic crisis, bone marrow infarction, osteomyelitis, splenic infarction & sequestration, dactylitis (children), gallstones, papillary necrosis, post-hyphaema glaucoma, retinal infarction. Chronic: chronic pain, chronic anaemia, leukocytosis, sickle nephropathy, sickle retinopathy, sickle hepatopathy, functional asplenia, leg ulcers, pregnancy, cardiac - pulmonary hypertension, cardiomegaly, diastolic heart failure, sickle lung disease, neurocognitive dysfunction, delayed puberty, erectile dysfunction, avascular necrosis, complications of pregnancy
