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Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
September 2010 exam. A 57-year-old female presents with headache, fever, neck stiffness with a positive Kernig's sign. CSF culture: Gram positive bacilli. What is the most likely causative organism? Listeria monocytogenes MRCPUK-parat-1-January 2013 exam: A 47-year-old lady with Feature of fever, headache and nuchal rigidity. Lumbar puncture reveals: Appearance: Cloudy. Glucose:1.7 mmol/l. Protein:1.9 g/l. White cells: 900 / mm³ (90% polymorphs). What is the most likely infective agent? Streptococcus pneumoniae (CSF results bacterial meningitis (low glucose, high protein, high polymorphs). In this age group Streptococcus pneumoniae and Neisseria meningitidis are the most common causes of bacterial meningitis) MRCPUK-parat-1-May 2014 exam: A diagnosis of pneumococcal meningitis is made. There are no other reports of meningitis in the local area over the past 4 weeks. How should the close contacts of this boy be managed? No action is needed (unless cluster of cases develop) MRCPUK-parat-1-May 2009 exam: A 23-year-old man is admitted with purpuric rash, pyrexia and confusion. His GP had given him intramuscular benzylpenicillin. Which one of the following investigations is most likely to reveal the diagnosis? Blood PCR for meningococcus (The blood cultures are likely to be negative as antibiotics have already been given. PCR has a sensitivity of over 90%)
Encephalitis Encephalitis usually presents with altered mental status, erratic behavior, etc (brain parenchyma involved). Aetiology • The most common cause is herpes simplex, usually type I (HSV-1).
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases Clinical Presentation • Altered mental status with fever and headache is the primary clue to the diagnosis. • Neck stiffness similar to that found in meningitis can occur, making it difficult to distinguish encephalitis from meningitis. • Seizures may also occur. Diagnosis • Although CT or MRI scan of the head should be performed, it cannot give a specific diagnosis. HSV has a predilection for involvement of the temporal lobes, which can sometimes be seen on CT. • A lumbar puncture is the key to the diagnosis. • PCR (polymerase chain reaction) for HSV has a 98% sensitivity and >95% specificity, making it at least equal to the biopsy. Treatment • HSV encephalitis is best treated with IV acyclovir. • Acyclovir-resistant herpes is treated with foscarnet
Meningococcal septicaemia Overview • It is associated with a high morbidity and mortality unless treated early • meningococcal disease is the leading infectious cause of death in early childhood. • A high index of suspicion is therefore needed. Presentation of meningococcal disease: • 15% - meningitis • 25% - septicaemia • 60% - a combination of meningitis and septicaemia Investigations • blood cultures • blood PCR • lumbar puncture is usually contraindicated • full blood count and clotting to assess for disseminated intravascular coagulation Management • the most important initial step administration of intravenous antibiotics (cefotaxime) is the greatest priority, regardless of whether cultures have been sent.
Sepsis Overview • Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. • Sepsis with shock is a life-threatening condition that is characterised by low blood pressure despite adequate fluid replacement, and organ dysfunction or failure. Definition • The new definition attempts to draw upon up-to-date pathobiology and distinguish between sepsis and uncomplicated infection. A new tool has been developed for this purpose - the SOFA or qSOFA. The qSOFA (Quick SOFA) criteria are:
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Respiratory rate > or equal to 22/min Altered GCS Systolic blood pressure < or equal to 100mmHg • Septic shock is defined as "a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to substantially increase mortality. This changes from the previous definition to recognise the importance of cellular abnormalities. • Septic shock is defined by persisting hypotension requiring vasopressors to maintain a mean arterial pressure of 65 mm Hg or higher and a serum lactate level greater than 2 mmol/L (18 mg/dL) despite adequate volume resuscitation. Risk factors for sepsis • Age (< 1 year and > 75 years) • very frail people • Immunocompromised impaired immune function (eg, DM, splenectomy, sickle cell disease) drugs( long-term steroids, chemotherapy, immunosuppressant) • surgery, or other invasive procedures, in the past 6 weeks • any breach of skin integrity (eg, cuts, burns, blisters or skin infections) • misuse drugs intravenously • indwelling lines or catheters
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
Risk stratification tool for adults, children and young people aged 12 years and over with suspected sepsis High risk criteria Moderate to high risk criteria Objective evidence of new altered mental state • History from patient or relative of new onset of altered behaviour or mental state • History of acute deterioration of functional ability • Impaired immune system (illness or drugs including oral steroids) • Trauma, surgery or invasive procedures in the last 6 weeks • respiratory rate: ≥25 breaths per minute • New need for oxygen (more than 40% FiO2) to maintain saturation more than 92% (or more than 88% in known chronic obstructive pulmonary disease) Raised respiratory rate: 21–24 breaths per minute Systolic blood pressure ≤90 mmHg or more than 40 mmHg below normal Systolic blood pressure 91–100 mmHg heart rate: > 130 beats per minute heart rate: 91–130 beats per minute (for pregnant women 100–130 beats per minute) or new onset arrhythmia Not passed urine in previous 18 hours. For catheterised patients, passed less than 0.5 ml/kg of urine per hour Not passed urine in the past 12–18 hours For catheterised patients, passed 0.5– 1 ml/kg of urine per hour
Tympanic temperature less than 36°C • Mottled or ashen appearance • Cyanosis of skin, lips or tongue • Non-blanching rash of skin Signs of potential infection, including redness, swelling or discharge at surgical site or breakdown of wound. Low risk criteria: • Normal behavior • No high risk or moderate to high risk criteria met Temperature in suspected sepsis • Do not rely on fever or hypothermia to rule sepsis either in or out. • Some people with sepsis may not develop a raised temperature: older or very frail severely ill people having treatment for cancer young infants or children. • a rise in temperature can be a physiological response (eg: after surgery or trauma). Management • 1 or more high risk criteria: blood test for blood gas including glucose and lactate measurement, blood culture, full blood count, C-reactive protein, urea and electrolytes, creatinine, clotting screen. Sepsis may be complicated by disseminated intravascular coagulation
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
give a broad-spectrum antimicrobial at the maximum recommended dose without delay (within 1 hour) • Any high risk criteria and lactate > 4 mmol/litre, or systolic BP < 90 mmHg: I.V fluid bolus without delay (within 1 hour) refer to critical care for review of management including need for central venous access , inotropes or vasopressors. • Any high risk criteria and lactate between 2 and 4 mmol/litre: I.V fluid bolus without delay (within 1 hour) Any high risk criteria and lactate < 2 mmol/litre: consider I.V fluid bolus • Failure to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation Failure to respond is indicated by any of: systolic blood pressure persistently below 90 mmHg reduced level of consciousness despite resuscitation respiratory rate over 25 breaths per minute or a new need for mechanical ventilation lactate not reduced by more than 20% of initial value within 1 hour. • 2 or more moderate to high risk criteria blood test for blood gas including glucose and lactate measurement, blood culture, full blood count, C-reactive protein, urea and electrolytes, creatinine review the person's condition and venous lactate results within 1 hour • 2 or more moderate to high risk criteria and lactate > 2 mmol/litre or evidence of acute kidney injury: treat as high risk • 2 or more moderate to high risk criteria, have lactate < 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition cannot be identified: repeat structured assessment at least hourly review by a senior within 3 hours for consideration of antibiotics. • 2 or more moderate to high risk criteria, have lactate < 2 mmol/litre, no evidence of acute kidney injury and in whom a definitive condition or infection can be identified and treated: manage the definitive condition if appropriate, discharge • Intravenous fluids in people with suspected sepsis If patients over 16 years need intravenous fluid resuscitation, use crystalloids that contain sodium in the range 130–154 mmol/litre with a bolus of 500 ml over less than 15 minutes.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
Sepsis Resuscitation Bundle: Surviving Sepsis Campaign • Should begin immediately, but must be accomplished within the first six hours of presentation.
- Serum lactate measured.
- Blood cultures obtained prior to antibiotic administration.
- From the time of presentation, broad-spectrum antibiotics administered within three hours for ED admissions and one hour for non-ED ICU admissions.
- In the event of hypotension and/or lactate > 4 mmol/l (36 mg/dl): Deliver an initial minimum of 30 ml/kg of crystalloid (or colloid equivalent). Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg.
- In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/l (36 mg/dl): Achieve central venous pressure (CVP) of > 8 mm Hg. Achieve central venous oxygen saturation (ScvO2) of > 70%. H/O sepsis secondary to pneumonia. treated with 4.5 L sodium chloride 0.9%. blood pressure was 82/40 mmHg. In attempting to restore the blood pressure, what is the most appropriate intravenous therapy? noradrenaline (norepinephrine) Ref: www.mrcpuk.org/ Acute Medicine Specialty Certificate Examination/ sample questions
Tuberculosis (TB) Definition • TB is an infection caused by Mycobacterium tuberculosis that most commonly affects the lungs. • Mycobacterium tuberculosis: aerobic non-motile bacillus. classified as a Gram-positive organism Pathophysiology • Primary tuberculosis Bacilli are transported via lymphatics early in the disease process to regional lymph nodes to cause marked lymphadenopathy. Process after exposure to mycobacterium tuberculosis: 90 % of individuals with intact immunity control further replication of the bacilli, by either: Clearance or enter a "latent" phase (asymptomatic, but has the potential to become active at any time) 10% Progression to local pulmonary disease or dissemination occurs more frequently in those with poor immune responses, such as: HIV chronic kidney failure, poorly controlled diabetes mellitus,
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
immunosuppressive medications (including transplant recipients), young children (before the age of five), older adults. non-immune host who is exposed to M. tuberculosis may develop primary infection of the lungs. A small lung lesion known as a Ghon focus develops. The Ghon focus is composed of tubercle-laden macrophages. The combination of a Ghon focus and hilar lymph nodes is known as a Ghon complex in immunocompetent people the initial lesion usually heals by fibrosis. immunocompromised peoples may develop disseminated disease (miliary tuberculosis). Mycobacterium avium causes disseminated infection in patients with advanced HIV, typically when the CD4 count is less than 50 cells/mm3. Pleural and pericardial infections (which can result in effusions) occur at or shortly after primary infection. • Secondary (post-primary) tuberculosis Definition Reactivation of the initial infection if the host becomes immunocompromised Site of reactivation: Pulmonary: the most common site for secondary TB. generally, occurs in the apex of the lungs and may spread locally or to more distant sites. Extra-pulmonary: CNS (tuberculous meningitis - the most serious complication) Vertebral bodies (Pott's disease) Cervical lymph nodes (Scrofuloderma) Scrofuloderma occurs when the skin becomes involved by direct extension from an underlying tuberculous infection (usually lymphadenitis). Renal GIT Causes of immunocompromise: immunosuppressive drugs (e.g. Steroids) HIV malnutrition Features • Primary TB is usually asymptomatic • cough >2 to 3 weeks' duration, lymphadenopathy, fevers, night sweats, weight loss • Pulmonary complications of TB can include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction, malignancy, and chronic pulmonary aspergillosis. • TB may be associated with an inflammatory polyarthritis that may follow a similar pattern to rheumatoid arthritis
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
Transmission • Non-sputum producing patients are non-infectious . Only untreated smearpositive pulmonary TB is likely to be infectious. Screening • Mantoux test • Interferon-gamma blood test It is used in several specific situations such as: the Mantoux test is positive or equivocal people where a tuberculin test may be falsely negative (see below) Patients should be routinely screened for TB exposure before treatment with Etanercept with the tuberculin skin test Mantoux test (tuberculin test) (purified protein derivative (PPD) test) • Mechanism: It is a type IV, (delayed) hypersensitivity reaction. It is a cell mediated immune response (measures the T cell-mediated immune response to TB antigen) mediated by interferon-γ secreted by Th1 cells which in turn stimulates macrophage activity. Memory TH1 cells previously formed against M. tuberculosis recognize peptide: MHC class II complexes on the surface of antigen presenting cells Positive tuberculin test occurs between three weeks and three months after primary infection. • Indication: the main technique used to screen for latent tuberculosis. The most commonly used screening test for contacts of a patient with recently diagnosed TB • Method 0.1 ml of 1: 1,000 purified protein derivative (PPD) injected intradermally result read 2-3 days later The left forearm is typically used. • Interpretation Only the induration, not surrounding erythema, is used in the measurement and the longest diameter is measured in millimeters:
Diameter of induration Positivity Interpretation < 6mm Negative - no significant hypersensitivity to tuberculin protein 6 - 15mm Positive - hypersensitive to tuberculin protein
15mm Strongly positive - strongly hypersensitive to tuberculin protein False negative tests may be caused by: ( ↓reaction to tuberculin protein) miliary TB sarcoidosis immunosuppression (HIV, corticosteroids) lymphoma very young age (e.g. < 6 months) Viral infections, live viral vaccines poor nutrition. Active disease may be indicated by grade III/IV response to tuberculin. 8% of individuals with history of BCG vaccination have grade I/II response. Which cytokines is most involved in the response of a Mantoux test? Interferon-γ BCG • Definition a live attenuated vaccine derived from a strain of Mycobacterium. bovis. • Benefits BCG is 70-80% effective against severe TB infection. Protection is thought to last for 10-15 years, with greater efficacy in the under 16 years population. it also has effects against leprosy ( Mycobacterium (M. leprae)) (up to 80% protection) BCG is currently used as a form of immunotherapy for treating bladder cancer; which can lead to disseminated M. bovis infection (systemic 'BCG-it is') • Indications should be given to neonates in high risk groups. Previously unvaccinated individuals A Mantoux should be documented before administration. Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Previously unvaccinated individuals may be given the BCG Should not be given BCG. May be due to previous TB infection or BCG or atypical mycobacteria. However, in other contexts (e.g. immigrant screening and contact tracing), further investigation and follow-up may be indicated. Suggests tuberculosis infection do chest x-ray
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
It should not be given to children who have a strongly positive tuberculin test new entrants from high‑ incidence countries and are previously unvaccinated (that is, without adequate documentation or a BCG scar) and are aged: younger than 16 years or 16–35 years from sub‑ Saharan Africa or a country with a TB incidence of 500 per 100,000 or more. healthcare workers Mantoux‑ negative contacts of people with pulmonary and laryngeal TB if they: have not been vaccinated previously and are aged 35 years or younger or are aged 36 years and older and a healthcare or laboratory worker who has contact with patients or clinical materials. • Contraindications BCG is a life attenuated vaccine containing M bovis, it should therefore be avoided in the immunosuppressed population. In case of increased risk of HIV, NICE advises that an HIV test should be done prior to vaccination. Diagnosis • definitive diagnosis isolation of Mycobacterium tuberculosis from a bodily secretion (eg, culture of sputum, bronchoalveolar lavage, or pleural fluid) or tissue (pleural biopsy or lung biopsy). Send multiple respiratory samples (3 deep cough sputum samples, preferably including 1 early morning sample) for TB microscopy and culture. If spontaneous sputum (by coughing) is difficult: Sputum may be induced by inhalation of hypertonic saline generated by a nebulizer. If patient is unable to produce sputum, bronchoscopy with bronchial washings for microscopy staining and culture is the investigation of choice. In children who are unable to cough up sputum, the gold standard is gastric washings for M tuberculosis culture Tissue biopsy may establish a definitive diagnosis of TB when other diagnostic techniques are not diagnostic. • probable diagnosis: can be based on: Typical clinical and chest X-ray findings, together with either sputum (or other specimens) positive for acid-fast bacilli, stains very weakly on testing. When using the Ziehl-Neelsen test it stains bright red against a blue background. typical histopathological findings on biopsy material • Smear-positive tuberculosis highly infectious (Patient needs treatment and isolation from casual contacts, his close contacts need screening) • Culture-positive tuberculosis means the immediate smear is negative, but prolonged culture has shown tuberculosis.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Management (NICE guidelines 2016)
•
If there are clinical signs and symptoms consistent with a diagnosis of TB, start
treatment without waiting for culture results.
Consider completing the standard recommended regimen even if subsequent
culture results are negative.
•
Should only be carried out in hospitals with appropriate isolation facilities.
Smear-positive tuberculosis means the patient is highly infectious to both
close contacts (more than 8 hours spent together per day) and casual
contacts, such as other patients on the ward and healthcare workers.
He therefore needs to be isolated in a negative-pressure room,
contacts should wear particulate masks until he has received anti-tuberculous
therapy for 2 weeks. The sputum might remain positive after this time, but the
organisms will be dead.
•
Length of treatment:
All forms of pulmonary TB may be treated equally except tuberculous pleural
effusion which may require drainage (with large effusions causing
breathlessness) and adjunct corticosteroids to delay reaccumulation.
A 6-month course of treatment is adequate for all non-CNS disease.
Length of treatment for other forms are:
bone TB – 6 months
Treatment for bone and joint tuberculosis is recommended to
continue for 2 months with the initial phase consisting of
quadruple therapy and the remaining 4 months of dual therapy.
It is recommended not to extend treatment for residual
complications such as collapsed discs or bending of the spine,
although there is some debate about this.
meningitis - 1 year
Antituberculous treatment for 12 months is recommended
for TB meningitis.
drug resistance - 2 years.
Treatment must be continued for a minimum of 18 months, with at
least 9 months of treatment after the patient becomes
culture-negative.
•
TB with strider:
If patient of TB presents with worsening breathlessness and stridor due to
mediastinal lymph nodes compressing the carina, the next step - after
commencing steroid - is urgent (CT) scan, first to confirm the degree of
airway compression and second to assess the response to chemotherapy.
•
Patients on long term steroids with TB:
Patients on long term steroids should have their dose of steroids
increased when starting antituberculous therapy.
The metabolism of corticosteroids is increased by rifampicin.
(P450 inducer)
•
Failing regimen in the treatment of TB:
reactivation of (TB) infection during treatment course.
Evidence of failing treatment:
worsening symptoms,
elevated C-reactive protein,
progression of chest X-ray changes
what is the most appropriate next treatment step?
Most guidelines recommend progression to five agents – rifampicin,
pyrazinamide, isoniazid, ethambutol and streptomycin.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
TB Drug therapy Treatment for active tuberculosis is: • Initial phase - first 2 months (RIPE)
- Rifampicin
- Isoniazid
- Pyrazinamide
- Ethambutol (the 2006 NICE guidelines now recommend giving a 'fourth drug' such as ethambutol routinely - previously this was only added if drug-resistant tuberculosis was suspected) either ethambutol or streptomycin. • Continuation phase - next 4 months
- Rifampicin
- Isoniazid After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampicin are continued as daily or intermittent therapy for 4-or-more months. Therapy must be extended if the patient has cavitary disease or remains culture positive after 2 months of treatment. Treatment for latent tuberculosis • isoniazid alone for 6 months Treatment for meningeal tuberculosis • treated for a prolonged period (at least 12 months) • 4 drugs for the first 2 months, followed by isoniazid and rifampicin 10 months. • addition of steroids (equivalent to prednisolone 20-40 mg) is recommended for the first 2-3 weeks, then with gradual reduction. (use of steroids is recommended to ensure adequate brain penetration and to prevent cranial nerve compression by meningeal scarring. Directly observed therapy • with a three times a week dosing regimen may be indicated in certain groups, including: homeless people with active tuberculosis patients who are likely to have poor concordance all prisoners with active or latent tuberculosis Tuberculosis: drug side-effects and mechanism of action • Rifampicin mechanism of action: inhibits bacterial DNA dependent RNA polymerase preventing transcription of DNA into mRNA mechanism of resistance for rifampicin resistant Mycobacterium tuberculosis Mutations in rpoB gene cause alterations in the bacterial DNA dependent RNA transcriptase, which prevents the binding of rifampicin. In patients with HIV/TB co-infection: Rifampicin is a potent inducer of liver enzymes (cytochrome P450). Furthermore, it up-regulates the expression of P-glycoprotein in the gastrointestinal tract. Co-administration of a protease inhibitor with rifampicin therefore will often lead to sub-therapeutic levels of the protease inhibitor.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
the British HIV Association suggest the substitution of rifampicin for an alternative rifamycin agent (rifabutin or rifapentine), which has less inducing action of cytochrome P450 Side effects potent liver enzyme inducer hepatitis, orange secretions (Red or orange discoloration of the urine and other body fluids) flu-like symptoms Rifampicin and isoniazid can cause a relative vitamin D deficiency • Isoniazid mechanism of action: Prevents cell wall synthesis by inhibiting the synthesis of mycolic acid Bactericidal Side effects Hepatotoxicity INH is the most common drug associated with toxicity. INH metabolites are responsible for INH hepatotoxicity N-acetyltransferase 2 (NAT2) is the primary enzyme that contributes to INH metabolism. NAT2 deficiency increases the risk of INH-induced liver injury. slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Peripheral neuropathy: Isoniazid-related demyelinating peripheral neuropathy relatively acute onset typically presents with reduced sensation +/- absent reflexes in lower limbs. prevented with low dose pyridoxine (Vitamin B6) treated with high-dose Pyridoxine agranulocytosis Drug-induced lupus erythematosus liver enzyme inhibitor isoniazid toxicity Risk factors alcoholism diabetes malnutrition, HIV, renal failure, neurotoxic medications, and pregnancy. Treatment high-dose pyridoxine, (low dose pyridoxine is used for prophylaxis). stopping or reducing the dose of isoniazid control of other risk factors (e.g. reduced alcohol intake, improved glycaemic control etc) INH Injures Neurons and Hepatocytes
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
• Pyrazinamide mechanism of action: converted by pyrazinamidase into pyrazinoic acid which in turn inhibits fatty acid synthase (FAS) Bactericidal Streptomycin has high activity against extracellular organisms whilst pyrazinamide have high activity against intracellular organisms. side effects hyperuricaemia causing gout arthralgia, myalgia the most common cause of arthralgia after starting antituberculous Hepatotoxicity • Ethambutol mechanism of action: Prevents cell wall synthesis by inhibiting arabinosyltransferase (which polymerizes arabinose into arabinan) Bacteriostatic side effects optic neuritis: check visual acuity before and during treatment Ocular side-effects of ethambutol Loss of acuity Colour blindness Restriction of visual fields dose needs adjusting in patients with renal impairment Ethambutol is renally excreted and therefore dose adjustment is necessary to minimise the risk of toxic effects (optic neuropathy). The remaining drugs are mainly metabolised in the liver and can be given in normal doses in renal failure. • Anti-tuberculosis drug and LFTs : All tuberculosis patients should have pre-treatment LFTs. rifampicin/isoniazid/pyrazinamide all are associated with liver toxicity, but isoniazid are most commonly implicated (this fact are tested in MRCPI website -part 1, sample question) Up to 20% of the patients receiving isoniazid either in single or combination therapy develop transient asymptomatic elevation in liver enzymes, which settle with continued use of the drug. while some patients (less than 1%–3%) develop severe liver injury and even liver failure If there is no pre-existing liver disease, LFTs are only repeated (and treatment stopped) if fever, malaise, vomiting , jaundice or unexplained deterioration occurs during treatment. Regular LFTs should be performed in patients with previously known chronic liver disease. define hepatotoxicity rifampicin/isoniazid/pyrazinamide should be stopped If AST/ALT levels rise by 5 times upper limit of normal range without symptoms
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
If ALT/AST levels rise by 3 times upper limit of normal range with symptoms (abdominal pain, nausea, vomiting, unexplained fatigue or jaundice) If the patient is not unwell and/or has non-infectious TB, no treatment until LFT returns to normal. If clinically unwell or sputum smear is positive within two weeks of starting treatment, consider streptomycin and ethambutol until LFT returns to normal. Once LFT is back to normal, challenge dosages can be reintroduced sequentially in order of isoniazid, rifampicin and pyrazinamide with daily monitoring of patient's condition and LFT. If there is a further reaction , the offending drug should be excluded and a suitable alternative regimen used. • Immune reconstitution disease Immune reconstitution inflammatory syndrome (IRIS) (also known as immune recovery syndrome) is a condition seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse occurs typically 3-6 weeks after starting treatment often presents with enlarging lymph nodes
Latent tuberculosis infection (LTBI) Definition • screening tests indicating previous infection with M. tuberculosis are positive without any pathological findings on radiological imaging. Epidemiology • Approximately 30% of persons exposed to Mycobacterium tuberculosis will develop LTBI and, if untreated, approximately 5% to 10% of these persons will progress to active tuberculosis disease or reactivation of tuberculosis. Risk for developing active tuberculosis • The lifetime risk of reactivation TB for a person with LTBI is about 5–10%. • Risk factors for developing active tuberculosis include: silicosis chronic renal failure HIV positive solid organ transplantation with immunosuppression intravenous drug use haematological malignancy anti-TNF treatment previous gastrectomy Diagnosis • Mantoux tuberculin skin test (TST) can be positive with both active and latent TB but can also by a previous BCG vaccination. Recommended for close contacts of a person with TB.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
If positive (induration ≥ 5 mm, regardless of BCG history) assess for active TB • Interferon gamma release assay (IGRA) Indications Quantaferon testing (interferon gamma testing) is recommended as a secondline test for people whose Mantoux testing may be less reliable - for example, BCG-vaccinated people. If the Mantoux test is positive + active TB is excluded, and evidence of infection is needed to decide on treatment. for example: if the person needs enhanced case management or if there could be adverse events from treatment. For immunocompromised, ( HIV and CD4 < 200 cells/mm3, or after transplant),Interferon‑ gamma release assay and a concurrent Mantoux test: If either test is positive assess for active TB. If assess for active TB is negative, treatment for latent TB infection. Advantage Quantaferon testing is not influenced by BCG vaccination status A positive test would, therefore, indicate prior exposure to M. tuberculosis (active or latent TB) Disadvantage The main disadvantage of the IGRA is its inability to distinguish between active and latent TB. • Chest x-ray NO TB-related findings on chest x-ray (e.g., hilar lymphadenopathy, upper lobe opacification, or cavitation), Treatment (NICE guidelines 2016) • Treatment of LTBI can reduce the risk of development of disease by 90% • For adults between the ages of 35 and 65 years, offer drug treatments only if hepatotoxicity is not a concern. • test for hepatitis B, C and HIV before starting treatment for latent TB. • NICE now give two choices for treating latent tuberculosis: 3 months of isoniazid (with pyridoxine) and rifampicin For people younger than 35 years if hepatotoxicity is a concern after an assessment of both liver function (including transaminase levels) and risk factors. 6 months of isoniazid (with pyridoxine) if interactions with rifampicin are a concern, for example, in people with HIV or who have had a transplant. NICE advises that once a diagnosis of pulmonary TB has been made then close contacts should be managed as follow: • If asymptomatic and younger than 65 years, then: test for latent TB. If Mantoux-negative and unvaccinated then offer vaccination. If at risk of HIV then test for HIV first (HIV testing and if negative, then BCG vaccination). • If asymptomatic and older than 65 years then assess with a chest X-ray.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Miliary TB Overview • miliary TB most likely occur in young children. Features • presents with a gradual onset of vague ill health, loss of weight and then fever. • TB meningitis 15 - 20% of patients who have miliary TB also have TB meningitis at the time of presentation. 33% of patient with TB meningitis have concomitant miliary TB. • Hepatosplenomegaly is seen in advanced disease. • Choroidal tubercles can be seen in the eyes. Investigations • tuberculin test is often negative. negative in up to half of patients with severe disease • chest x ray may be normal in up to one third of patients. The classic millet seed nodules are small measuring about 1-2 mm. • Not all patients will be sputum positive and with evidence supporting a diagnosis of tuberculosis treatment should be commenced swiftly. • Transbronchial biopsy – positive at an early stage. • Biopsy of liver and bone marrow might be required. Milliay TB
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
Non-tuberculous mycobacterial infections Opportunistic mycobacteria • Mycobacterium kansasii • Mycobacterium malmoense • Mycobacterium xenopi • Mycobacterium avium intracellular(The presence of acid fast bacilli (AFB) and absence of TB (Mycobacterium tuberculosis negative on culture.) suggests an atypical AFB such as M. avium.) The presence of AFB yet absence of TB suggests an atypical AFB such as M. avium. Mycobacterium avium causes disseminated infection in patients with advanced HIV, typically when the CD4 count is less than 50 cells/mm3. Mycobacterium malmoense • is a non-tuberculous mycobacterium • most commonly causes pulmonary infection in middle-aged and older adults with pre-existing lung disease or immunodeficiency and can also cause local invasion from a skin lesion. • It causes nonspecific symptoms, such as malaise and weight loss, or chest symptoms that take an atypical course. Pathophysiology • they can colonise structurally abnormal lung, for example in patients with: Cavitary disease Bronchiectasis Chronic obstructive pulmonary disease Such patients might not always require treatment. However, if treatment is required, then it is usually for longer than the standard 6 months needed to treat pulmonary tuberculosis • 'atypical' mycobacteria differ from M. tuberculosis in that they are ubiquitous organisms and have no person-to-person spread. • Mycobacterium marinum infection It is an uncommon atypical mycobacterium infection The skin is the most common site of infection, where it usually produces a solitary indolent granulomatous lesion - the 'fish tank granuloma'. usually seen in patients who handle fish or swim in freshwater or saltwater. occurs when contaminated water is exposed to skin that has experienced open trauma. fish tank granuloma' caused by Mycobacterium marinum
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Diagnosis • A single isolate from a non-sterile site might not be significant and can just represent contamination. More than two isolates from a non-sterile site are required to establish disease. • Chest X-ray => (like other mycobacterium) upper-zone fibrosis and cavitation. Treatment • No need to isolate patients or notify public health authorities.
Multidrug-resistant tuberculosis (MDR-TB). Definition • Defined as resistance to rifampicin and isoniazid, with or without resistance to other anti-TB drugs. • defined as positive cultures after 4 months of therapy. Epidemiology • Rare in previously untreated white patients born in the UK(< 2%). • Higher levels of resistance occur in Indian subcontinent and black, with isoniazid resistance occurring in 4-6% of such patients. Risk factors • Poor compliance (the most common reason) • Previous anti-TB treatment • Contact with a known case of drug-resistant TB • Birth in a foreign country, particularly high-incidence countries • HIV infection • Residence in London • Age profile, with highest rates between ages 25 and 44 • Male gender • Homelessness • Intravenous drug use • Infection acquired in institutions (eg prison) Treatment • Directly observed therapy is recommended • should be treated with an injectable agent such as amikacin, kanamycin or capreomycin, in combination with a fluoroquinolone and at least three other agents. At least 5 drugs, one of which is a quinolone, is the recommended • Ideally the injectable agent is administered daily for the first 6-8 months, forming an intensive phase of treatment, with other drugs then continued for a total of 18-24 months. • In practice, unwanted effects may lead to intravenous therapy being discontinued early.
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
Leprosy Definition • Leprosy is a granulomatous disease primarily affecting the peripheral nerves and skin. It is caused by Mycobacterium leprae. Features • patches of hypopigmented skin typically affecting the buttocks, face, and extensor surfaces of limbs • sensory loss Types • The degree of cell mediated immunity determines the type of leprosy a patient will develop: Low degree of cell mediated immunity → lepromatous leprosy ('multibacillary') extensive skin involvement symmetrical nerve involvement High degree of cell mediated immunity → tuberculoid leprosy ('paucibacillary') limited skin disease asymmetric nerve involvement Management • WHO-recommended triple therapy: rifampicin, dapsone and clofazimine • BNF advice: multibacillary leprosy (>6 lesions) rifampicin, dapsone and clofazimine for 12 months. paucibacillary leprosy (5 or less lesions) rifampicin and dapsone for 6 months.
Vaccinations
Live attenuated vaccines • BCG • measles, mumps, rubella (MMR) • oral polio • oral rotavirus • oral typhoid • influenza (intranasal) • yellow fever • Varicella Live attenuated vaccines are contraindicated in all HIV positive and immunocompromised patients. Inactivated preparations • rabies • influenza (intramuscular) Detoxified exotoxins • tetanus Extracts of the organism/virus (sometimes termed fragment) (may also be produced using recombinant DNA technology) • diphtheria • pertussis ('acellular' vaccine) • hepatitis B • meningococcus, pneumococcus, haemophilus
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Notes • influenza: different types are available, including whole inactivated virus, split virion (virus particles disrupted by detergent treatment) and sub-unit (mainly haemagglutinin and neuraminidase) • cholera: contains inactivated Inaba and Ogawa strains of Vibrio cholerae together with recombinant B-subunit of the cholera toxin • hepatitis B: contains HBsAg adsorbed onto aluminium hydroxide adjuvant and is prepared from yeast cells using recombinant DNA technology Contraindications to pertussis immunisation • Acute illness - until recovered • Previous reaction to pertussis:
- Local: an extensive area of redness and swelling which becomes indurated, involving most of the anterolateral surface of the thigh or a major part of the circumference of the upper arm
- General: fever equal to or more than 39.5°C within 48 hours of vaccine, anaphylaxis, bronchospasm, laryngeal oedema, generalised collapse, prolonged hyporesponsiveness, prolonged inconsolable or high-pitched screaming of more than four hours, convulsions or encephalopathy occurring within 72 hours. Splenectomised patients • Splenectomised patients are at increased risk of infection with: encapsulated bacteria A popular mnemonic to remember most of the encapsulated bacteria is the SHiNE SKiS bacteria (S. pneumo, Hib, N. meningitidis, E. Coli, Salmonella, Klebsiella, Group B Strep). infections that are filtered by the spleen (for example, malaria). • When elective splenectomy is planned, vaccines to pneumococcus and meningiococcus should be given two weeks pre-surgery to allow an antibody response to evolve. • Patients who have emergency splenectomies should be vaccinated post-operatively (most effective if performed at least 14 days after surgery) Prophylaxis in splenectomy • Following a splenectomy patients are particularly at risk from pneumococcus, Haemophilus, meningococcus and (Capnocytophaga canimorsus infections usually from dog bites) • Vaccination if elective, should be done 2 weeks prior to operation Hib, meningitis A & C annual influenza vaccination pneumococcal vaccine every 5 years • Antibiotic prophylaxis penicillin V: unfortunately clear guidelines do not exist of how long antibiotic prophylaxis should be continued. It is generally accepted though that penicillin should be continued for at least 2 years and at least until the patient is 16 years of age, although the majority of patients are usually put on antibiotic prophylaxis for life
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
MRCPUK-part-1-January 2018 exam: H/O emergency splenectomy. Following this he takes penicillin V on a daily basis. He is unsure of his vaccination history. Which organism is he particularly suscepitble to? Haemophilus influenza (Penicillin V would protect him against Streptococcus pneumoniae but notHaemophilus influenzae due to the production of beta-lactamases by the organism) MRCPUK-part-1-September 2019 exam: A 12-year-old boy who had a splenectomy following RTA , he had his full immunisation course as a child and was given a repeat pneumococcal vaccination 5 days following surgery. What is the most appropriate ongoing management? Booster dose of Hib and MenC vaccine + annual influenza vaccination + lifelong penicillin V
Post-exposure prophylaxis Hepatitis A • Human Normal Immunoglobulin (HNIG) or hepatitis A vaccine may be used depending on the clinical situation Hepatitis B • HBsAg positive source: if the person exposed is a known responder to HBV vaccine then a booster dose should be given. If they are in the process of being vaccinated or are a non-responder they need to have hepatitis B immune globulin (HBIG) and the vaccine • unknown source: for known responders the green book advises considering a booster dose of HBV vaccine. For known non-responders HBIG + vaccine should be given those in the process of being vaccinated should have an accelerated course of HBV vaccine. accelerated course of HBV vaccine given at zero, one and two months. For those who are at continued risk, a fourth dose is recommended at 12 months. Source person Exposed person HBsAg positive unknown responder to HBV vaccine booster HBV vaccine booster HBV vaccine non-responder (HBIG) + vaccine HBIG + vaccine in the process of vaccination (HBIG) + vaccine accelerated course of HBV vaccine (given at zero, one and two months) Hepatitis C • Monthly PCR - if seroconversion then interferon +/- ribavirin
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
HIV • Three antiretroviral agents for 1 month New guidelines in 2014 recommend three-agent PEP with Truvada® (tenofovir and emtricitabine) and raltegravir, which should both be taken for 1 month. (i.e. Within 1-2 hours, but may be started up to 72 hours following exposure) for 4 weeks • Serological testing at 12 weeks following completion of post-exposure prophylaxis • Reduces risk of transmission by 80% Varicella zoster • VZIG for IgG negative pregnant women/immunosuppressed Estimates of transmission risk for single needle stick injury Hepatitis B 20-30% Hepatitis C 0.5-2% HIV 0.3% First line management of needle stick injuries includes immediate washing of the affected area under running water. UK Guideline for the use of HIV Post-Exposure Prophylaxis Following Sexual Exposure (PEPSE) • If the source is of unknown status: → establish the HIV status of the source. • Source individual known to be HIV-positive: →determine the HIV viral load, resistance profile and treatment history. • if the source is on antiretroviral therapy (ART) with a confirmed and sustained (>6 months) undetectable plasma HIV viral load →PEPSE is no longer recommended
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
Chapter 9
Infectious diseases
However, if there are any doubts about the HIV viral load history or the source’s adherence to ART →PEP should be given following unprotected receptive anal intercourse. Initiation of PEPSE is recommended as soon as possible after exposure, preferably within 24 hours of exposure but can be offered up to 72 hours. The first-line regimen is Truvada and raltegravir Truvada → fixed-dose combination of two antiretroviral medications: tenofovir disoproxil and emtricitabine (both are Nucleoside analog reverse-transcriptase inhibitors (NRTIs) Raltegravir (integrase inhibitors, a new class of HIV drugs ) targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. PEPSE beyond 72 hours are not recommend duration of PEPSE should be 28 days follow-up HIV testing at 8-12 weeks after exposure pregnancy should not alter the decision to start PEPSE. Women must be counselled that antiretroviral agents used for PEPSE are unlicensed in pregnancy and risks / benefits must be carefully discussed In the event of a further high-risk sexual exposure in the last two days of the PEPSE course the PEP should be continued for 48 hours after the last high-risk exposure If the recipient has missed more than 48 hours of PEPSE then the course should be discontinued.
Brucellosis Overview • Brucellosis is a zoonosis more common in the Middle East and in farmers. • Gram negative bacilli • It is considered a class B bioterrorist agent, is easily spread by aerosol, and is a significant hazard in microbiology laboratories. • Four major species cause infection in humans: B melitensis (sheep), B abortus (cattle), B canis and B suis (pigs). • incubation period 2 - 6 weeks • Most cases of brucellosis in Northern Europe and North America are acquired overseas and/or from consuming unpasteurised milk products, including cheese. Features • non-specific: fever, (prolonged fever of unknown origin) malaise • hepatosplenomegaly • sacroilitis: spinal tenderness may be seen. Brucellosis is a recognised cause of spondylitis associated rheumatic features in about 50% of cases. • complications: osteomyelitis, infective endocarditis, meningoencephalitis, orchitis • leukopenia is common Diagnosis • the Rose Bengal plate test can be used for screening but other tests are required to confirm the diagnosis • Brucella serology is the best test for diagnosis • blood and bone marrow cultures may be suitable in certain patients, but these tests are often negative
Notes & Notes for MRCP
By Dr. Yousif Abdallah Hamad
75% have a positive blood culture (90% of bone marrow cultures will be positive). Management • doxycycline and streptomycin
Cat scratch disease (CSD) Definition: a benign, self-limiting infectious disease that is transmitted mainly by cats (via scratching, biting, or licking) Pathogen: Gram negative rod Bartonella henselae Features • fever, headache, malaise • history of a cat scratch • regional lymphadenopathy • In immunocompromised individuals (e.g., patients with HIV) → Bacillary angiomatosis (vascular proliferation, which leads to the development of solitary or multiple, red-purple papules that bleed easily). Treatment • Mild or moderate cases: azithromycin (5-day course) to decrease lymphadenopathy and the duration of illness • In the case of persistent and/or disseminated disease (e.g., bacillary angiomatosis): erythromycin OR doxycycline • In the case of CNS involvement or endocarditis: rifampicin PLUS either erythromycin OR doxycycline
Whooping cough (pertussis) Bacteria • caused by the bacterium Bordetella pertussis. • gram-negative aerobic coccobacillus The virulence factors of Bordetella pertussis include its eponymous toxin and tracheal cytotoxin, • grows best on Bordet-Gengou agar and Regan-Lowe medium (Bordet for Bordetella) Epidemiology • now more common in adolescents and adults than in children. Mechanism • The tracheal cytotoxin from Bordetella pertussis kills ciliated cells along the respiratory epithelium. • Pertussis toxin inactivates Gi, an inhibitory protein. Gi normally inhibits activation of adenylate cyclase. Therefore, the pertussis toxin inhibits an inhibitor leading to increased activity of adenylate cyclase. Pertussis toxin ↓ Gi ↑adenylate cyclase Features • Pertussis has three major phases: the catarrhal phase (like the common cold), the paroxysmal phase (bouts of coughing), and the convalescent phase (resolution). • Lymphocytosis is typically found. it causes a profound leucocytosis by inhibiting chemokines that normally remove white cells from the blood stream.
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