Malaria

Malaria is a tropical parasitic infection of the red blood cells caused by the protozoal species Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. It is transmitted through the bite of the female Anopheles mosquito. The average incubation period is twelve to fourteen days. Congenital and blood-borne transmissions can also occur. P. falciparum and P. vivax account for most human infections but almost all deaths are caused by P. falciparum, with children under five years of age bearing the brunt of morbidity and mortality in endemic countries. P. falciparum is dominant in sub-Saharan Africa whereas P. vivax predominates in Southeast Asia and the Western Pacific. P. ovalae and P. malaria are less common and are mainly found in sub-Saharan Africa. P. knowlesi primarily causes malaria in macaques and is geographically restricted to southeast Asia. While taking a blood meal, the female anopheline mosquito injects motile sporozoites into the bloodstream. Within half an hour, the sporozoites invade the hepatocytes and start dividing to form tissue schizonts. In P. vivax and P. ovale, some of the sporozoites that reach the liver develop into hypnozoites and stay dormant within the hepatocytes for months to years after the original infection. The schizonts eventually rupture releasing daughter merozoites into the bloodstream. The merozoites develop within the red blood cells into ring forms, trophozoites, and eventually mature schizont. This part of the life cycle takes twenty-four hours for P. knowlesi; forty-eight hours for P. falciparum, P. vivax, P. ovale; and seventy-two hours for P. malariae. In P. vivax and P. ovale, some of the sporozoites that reach the liver develop into hypnozoites and stay dormant within the hepatocytes for months to years after the original infection. The hallmark of malaria pathogenesis is parasite sequestration in major organs leading to cytoadherence, endothelial injury, coagulopathy, vascular leakage, pro-inflammatory cytokine production, and tissue inflammation. Malaria is the most frequently imported tropical disease in the UK with an annual case load of around 2000. P. falciparum is the predominant imported species, and failure to take chemoprophylaxis is the commonest risk factor.

Geographical Pattern of Infectious Diseases and Infection Prevention for Travellers

Infectious diseases are transmitted either directly from person to person via direct contact or droplet exposure, or indirectly through a vector organism (mosquito or tick) or a non-biological physical vehicle (soil or water). Vector-borne infectious diseases are highly influenced by climate factors such as temperature, precipitation, altitude, sunshine duration, and wind. Therefore, climate change is a major threat for the emergence and re-emergence of infectious diseases, e.g. re-emergence of dengue fever in some parts of southern Europe. The natural reservoirs of infectious diseases are either humans (anthroponoses) or animals (zoonoses). Population movement due to travel or civil unrest risks introducing non-immune populations to regions that are endemic for certain infectious diseases. By contrast, global trade contributes to the movement of animals or arthropods across the world and this poses a major risk for introducing infectious diseases to previously non-endemic settings, e.g. rats on board commercial ships and the global spread of hantaviruses; international trade in used car tyres and the risk of introducing flavivirus-infected mosquitoes into non-endemic settings; and the contribution of migratory birds to the introduction and the spread of West Nile virus in the United States. The unprecedented growth of international travel facilitates the swift movement of pathogens by travellers from one region to another. The main determinants of travel-related infections are destination country, activities undertaken during travel, and pre-existing morbidities. Therefore, the pre-travel consultation aims to assess potential health hazards associated with the trip, give advice on appropriate preventative measures, and educate the traveller about their own health. Attitudes towards seeking pre-travel health advice vary by the type of traveller. For example, those visiting friends and relatives (VFRs) in their country of origin are less likely to seek pre-travel health advice compared to tourists and therefore stand a higher chance of presenting with preventable infections such as malaria. The key aspects of a pre-travel consultation include: ● comprehensive risk assessment based on the demographic and clinical background of the traveller as well as the region of travel and itinerary.

Opportunistic Infections in HIV Infection

An infection is defined as opportunistic when it affects those with severe immunosuppression, i.e. takes a n opportunity to cause disease in a host with a weakened immune system. In people living with HIV it mainly affects those with a CD4 count < 200 although it is not impossible in those with CD4 count > 200. The CD4 percentage is also important as those with a CD4% < 14 are also more likely to have an OI. The lower the CD4 count the higher the risk of OIs, and some OIs are seen much more commonly with very low CD4 counts, e.g. cryptococcal meningitis in those with CD4 count of < 100. Before the introduction of antiretroviral therapy OIs were much more common than they are now, with previously up to 80% of those with AIDS having pneumocystis pneumonia (PCP). Since the introduction of antiretrovirals (ARVs) the rates of OIs has reduced greatly but unfortunately there are people who are still diagnosed late with an OI at diagnosis. Those with poor adherence or difficulty accessing ARVs are also more likely to be affected. In the UK in 2014, 40% of people diagnosed with HIV had a CD4 count of <350 which is defined as a late diagnosis (and 22% had a CD4 count of <200 which is defined as a very late diagnosis). In comparison to someone diagnosed with HIV early, those who are diagnosed late have a 10 times higher risk of dying in the year after they are diagnosed. This highlights the need for routine HIV testing so that people are diagnosed early to reduce the incidence of OIs further. The most common OIs seen in the UK are pneumocystis pneumonia (PCP), central nervous system (CNS) toxoplasmosis, cryptococcal meningitis, cytomegalovirus (CMV) retinitis, Mycobacterium avium intracellulare (MAI) infection and candidiasis. All those with HIV and a CD4 count ≤ 200, or with a CD4% < 14 should be given prophylaxis against PCP. Prophylaxis should also be recommended for those with oral candidiasis or a previous AIDs – defining illness. The options are co-trimoxazole 480mg od or 960mg 3x/week (960mg once daily can be given although does not confer any greater protection and has increased risk of side effects), dapsone 50mg once daily, or pentamidine nebulisers 300mg once every 4 weeks.

Vaccination Schedules

The vaccines included in the current UK Immunisation Schedule offer protection against the following pathogens: A. Viruses ● Measles ● Mumps ● Rubella ● Polio ● Human Papilloma Virus (certain serotypes) ● Rotavirus ● Influenza virus (flu A and B) ● Varicella zoster virus (shingles) ● Hepatitis B virus B. Bacteria ● Corynebacterium diphtheriae (Diphtheria) ● Clostridium tetani (Tetanus) ● Bordetella pertussis (Pertussis) ● Haemophilus influenzae type B (Hib) ● Neisseria meningitidis (Meningococcal disease—certain serotypes) ● Streptococcus pneumoniae (Pneumococcal disease—certain serotypes) The UK Immunisation Schedule has evolved over several decades and reflects changes in vaccine development and commercial availability, national and sometimes international disease epidemiology, and the latest expert opinion. It is designed to offer optimal protection against infectious diseases of childhood to infants and children at the most appropriate age. The most up-to-date information about the UK Immunisation Schedule is available on the online version of the Department of Health publication commonly known as the ‘Green Book’: Immunisation Against Infectious Disease Handbook (see Further reading. Various chapters of the online version are updated at regular intervals; thus, it is very important to refer to the online version of the Green Book on the website for current guidance. Changes to the UK Immunisation Schedule are made on the recommendation of the independent Joint Committee on Vaccines and Immunisation (JCVI). Several of the UK Immunisation Schedule vaccines are combined vaccines: ● Measles, mumps, and rubella (MMR). ● Hexavalent diphtheria, tetanus, acellular pertussis, inactivated polio virus, Haemophilus influenza type b, hepatitis B (DTaP/IPV/Hib/HepB). ● Diphtheria, tetanus, acellular pertussis, inactivated polio, and Haemophilus influenzae (DTaP/IPV/Hib). ● Diphtheria, tetanus, acellular pertussis, inactivated polio (DTaP/IPV). ● Tetanus, diphtheria, and inactivated polio (Td/IPV). ● Inactivated influenza vaccine: influenza A H1N1, H3N2, influenza B. ● Live attenuated intranasal influenza vaccine: influenza A H1N1, H3N2, influenza B. In the UK, vaccines against single pathogens covered by the MMR vaccine are not recommended and not available in the National Health Service (NHS). There has been some limited demand for single-target vaccines, e.g. measles, due to misguided and unfounded concerns about the alleged risks of autism following MMR.

Outpatient Parenteral Antimicrobial Treatment (OPAT)

Outpatient parenteral antimicrobial therapy (OPAT) is the provision of intravenous (IV) antibiotics to patients in the community or an ambulatory care setting. It was first used to treat children with cystic fibrosis in the 1970s but did not become part of adult services in the UK until the 1990s. OPAT facilitates hospital admission avoidance and decreased lengths of inpatient stay. It is associated with high levels of patient satisfaction. Recent clinical guidelines on the provision of OPAT services in the UK and US have recently been published Skin and soft tissue infections (SSTIs), in particular lower limb cellulitis, are the commonest medical conditions referred to OPAT services. Patients are typically treated for three to five days with IV antibiotics but patients with lymphoedema or underlying skin conditions typically require longer courses. Increasingly, multidrug-resistant urinary tract infections (UTIs) may be treated in the community with IV antibiotics, although oral options such as fosfomycin are now available. Patients with bone and joint infection invariably require prolonged parenteral antibiotic courses, whether this be vertebral osteomyelitis or native or prosthetic joint infection. Other less common examples, where careful patient selection is required, include infected diabetic foot ulcers (with or without osteomyelitis), infective endocarditis, empyema, liver, and tubo-ovarian and brain abscesses. Patients are recruited on the basis of clinical syndromes (e.g. lower limb cellulitis) or laboratory referral (e.g. multidrug-resistant UTIs). Active recruitment (e.g. attendance at acute assessment unit board rounds or orthopaedic multidisciplinary teams, MDTs) compared to passive recruitment (waiting for clinical referrals) increases the yield of patients. The suitability of a patient to receive treatment out of hospital or in an ambulatory care setting needs careful assessment and is dependent upon age, comorbidities, and severity of infection. OPAT also requires patients to engage actively and reliably with therapy. Therefore, IV drug users and patients with serious mental health problems are generally not suitable. Commonly used antibiotics are those given once daily as these reduce nursing time, although some nursing teams can administer IV antibiotics up to three times per day. It is imperative to take a drug allergy history and seek an alternative class of antibiotics when a patient complains of severe penicillin allergy.

Detecting Antimicrobial Resistance

● To optimize antimicrobial therapy for the management of individual patient’s infection. ● For surveillance purposes, which in turn inform local/national/international clinical guidelines. ● For the management of infection control and prevention. Broadly speaking, resistance is detected by observing its phenotypic expression (activity of the candidate drug(s) against the target bacterium) or detecting the underlying genotypic determinant (resistance genes). Commonly used methods in clinical diagnostic laboratories generally fall under the ‘phenotypic’ category. These share similar traits— ease of use, reproducibility, scalability, quick turnaround of results and relative low cost of materials/reagents required. Moreover, decades of experience and fine-tuning have seen them established as methods of choice in most microbiology laboratories. Most phenotypic test methods are reliant on the use of clinical breakpoints set by national and international bodies (e.g. EUCAST and CLSI) to determine susceptibility/resistance. These guidelines are regularly subject to updates with input from leading experts and latest research findings. It is important for clinical diagnostic laboratories to adhere to best practice guidance set out by these bodies and keep up-to-date with the latest guidelines. Growth characteristics (on artificial media) of the bacterium of interest are extremely important in conventional phenotypic methods. As this presents a big obstacle for slow growers and ‘unculturable’ pathogens (e.g. Mycobacterium tuberculosis, Mycoplasma spp.) it has led to the introduction of genotypic methods of resistance detection in the clinical diagnostic laboratory. meteoric rise in the world of microbiology. Compared with conventional phenotypic methods, molecular genotypic-based tests are better suited for automation and reduce dependence on skilled workers for result interpretation. They therefore deliver the rapid turnaround demanded by modern medicine. Antimicrobial susceptibility tests (ASTs) is a term used to describe a range of phenotypic methods that employ direct observation of the action of antimicrobials against a target microorganism. This is the most commonly used method in clinical diagnostic laboratories for detecting resistance in bacteria. A. Disc diffusion Growth medium: Standardized agar plates (usually unsupplemented, but addition(s) may be necessary for bacteria with specific growth requirements). Antibacterial component: Fixed dose in standard size circular paper discs or tablets.

Infection of the Central Nervous System

Meningism is the syndrome of the triad of symptoms of headache, neck stiffness, and photophobia caused by irritation of the meninges. While it is often associated with a diagnosis of meningitis, it is also present in other conditions causing meningeal irritation such as subarachnoid haemorrhage, trigeminal neuralgia, migraine, or febrile illness in children. Meningitis is process of inflammation of the meninges, which may or may not be due to an infectious agent. Strictly speaking, it is a pathological diagnosis, but in lieu of the impracticability of biopsying the meninges, surrogate markers are used to infer inflammation. These include raised cerebrospinal fluid (CSF) white cell count and protein; and meningeal enhancement using contrast enhanced MRI or CT of the brain. Encephalitis is process of inflammation of the brain parenchyma. Strictly speaking, it is again a pathological diagnosis, and again surrogate markers are used to infer this inflammation, although it is slightly more difficult due to the protected nature of the brain. CSF white cell count and protein are expected to be elevated and parenchymal inflammation may be seen on contrast enhanced MRI. Meningoencephalitis is a combination of the above with inflammation of both the meninges and the adjoining brain parenchyma. Aseptic meningitis is said to be present when there is meningism and signs of meningeal inflammation on CSF and imaging, but no bacterial cause is found on culture or molecular diagnostics. Viral meningitis is the commonest cause, although post-neurosurgical aseptic meningitis is often chemical in nature. Meningism plus fever are the classic symptoms of meningitis. The onset may be acute, subacute, or chronic, depending on the cause. Neck stiffness may range from mild discomfort to an almost rigid neck and is not a sensitive test in young children or elderly. While not used routinely and with low sensitivity particularly in young children and elderly, Kernig’s and Brudkzinski’s signs, both of which stretch the meninges worsening the irritation and increasing pain, have a good positive predictive value. Non-specific signs of intracranial pathology may be present, such as signs of raised intracranial pressure (ICP), vomiting, reduced level of consciousness, focal neurological signs, seizures, or irritability, especially in the immunocompromised, elderly, and young children who may not have classic signs and symptoms.

Gastro-intestinal, Hepatic, Pancreatic, and Biliary Infections

The gastro-intestinal tract (GIT) hosts the most numerous and diverse reservoir of microbes in humans. There is increasing interest in the relationship between the GIT microbiome and human health. Obesity, diabetes, allergy, and a number of inflammatory diseases have been linked with the human GIT microbiome. Infections of the GIT arise either as a result of a change in the relationship between the commensal microbes colonizing the GIT (endogenous infection) or entry in to the GIT of a micro-organism which causes disease (exogenous infection). Commensals most commonly invade host tissues as a result of compromised defensive barriers. Disease associated with exogenous infection can be toxin-mediated, or associated with local or systemic invasion of the host. Endogenous infections are usually polymicrobial. In the mouth the aetiology, presentation, and anatomical associations have led to the description of a number of syndromes. Peritonsillar infection with involvement of the internal jugular vein is Lemierre’s syndrome, which is particularly associated with infection with Fusobacterium necrophorum. ‘Trench mouth’ is a severe form of ulcerative gingivitis, so named because in the absence of oral hygiene it was a relatively common diagnosis among those in the trenches during the First World War. Ludwig’s angina is a severe infection of the floor of the mouth which spreads in to the submandibular and sub-lingual space, often following a tooth-related infection. Deep neck infections are more common in children than adults and can involve the parapharyngeal, retropharyngeal, peri-tonsillar, or sub-mandibular spaces. Children with deep neck infections are more likely than adults to present with cough and respiratory distress. Oesophagitis has a wide range of potential aetiologies. Fungi (particularly Candida species) are probably the most common microbial cause of oesophagitis. Fungal infection of the distal oesophagus is thought to play an important role in the pathogenesis of disseminated fungal infection. Risk factors for fungal infection include poor oral intake, exposure to antibiotics, immunocompromise (HIV, steroids, cancer treatments), gastric acid suppressants, and damage to mucosal integrity (naso-gastric tubes, acid reflux, varices). Bacteria (including Mycobacteria, Actinomycetes, Treponemes), parasites, and viruses (herpes simplex, cytomegalovirus) are rarer infectious causes of oesophagitis.

Upper and Lower Respiratory Tract Infections

Pharyngitis is common with incidence peaking from autumn to spring. Respiratory viruses are most commonly implicated, and are generally self-limiting conditions not requiring diagnostic workup or treatment. Bacterial pharyngitis is less common, is spread by droplets or direct transmission, and Streptococcus pyogenes (Group A strep, or GAS) is the most frequent cause. Haemophilus influenzae, Mycoplasma pneumoniae, and Neisseria gonorrhoeae are less frequent causes. Rapid antigen detection tests make the point-of-care assessment of GAS pharyngitis possible, although a negative test does not exclude infection. No method can distinguish oropharyngeal colonization from actual infection, but culture can obtain antibiotic susceptibility testing. Suspicion of infection with Neisseria gonorrhoeae, Bordetella pertussis, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydophila pneumoniae, or Corynebacterium diptheriae should be communicated to the laboratory so that the appropriate culture media is utilized. The Centor criteria provide a clinical predictive score that can give the likelihood a sore throat is due to a bacterial infection with the following: the presence of tonsillar exudate, tender anterior cervical adenopathy, fever over 38°C, and absence of cough. If three or four of these criteria are met, the positive predictive value is 40% to 60%. The absence of three or four of the Centor criteria has a relatively high negative predictive value of 80%, and may be use to evaluate whether antibiotics can be withheld or deferred. Oral penicillin or macrolide are used to treat streptococcal pharyngitis. Treatment may reduce severity, duration, transmission, and risk of post-infectious sequelae like rheumatic heart disease and post-streptococcal glomerulonephritis. Other complications include scarlet fever, streptococcal toxic shock syndrome, and quinsy. Otitis media, is frequent in the young children, possibly due to a short and horizontal Eustachian tube. Purulent material buils up leading to a bulging, red tympanic membrane which may rupture and discharge. Intense local pain and fevers may occur. Streptococcus pneumoniae, Moraxella catarrhalis, and Haemophilus influenzae are frequently implicated. Frequently there are no sequelae, although complications include hearing impairment, and less common are mastoiditis, bacteraemia, and meningitis. Diagnosis is clinical based on presentation and otoscopic examination. Microbiological diagnosis is possible through culture of exuate on swab or following tympanocentesis.

Bone and Joint Infections

Patients with bone and joint infections can present with native joint septic arthritis, osteomyelitis, or implant-associated bone and joint infections. Patients often present with an acute onset of hot, swollen, painful joint with restricted function in one or more joints over a couple of weeks. On examination the affected joint is painful with a limited range of movement, and fever is present. Risk factors for septic arthritis include an abnormal joint architecture due to pre-existing joint disease, e.g. patients with rheumatoid arthritis, or patients on haemodialysis, with diabetes mellitus, or older than 80 years of age. The differential diagnosis includes reactive arthritis, pre-patellar bursitis, gout, Lyme disease, brucellosis, and Whipples disease. Staphylococcus aureus is the most common cause of septic arthritis, followed by Group A streptococcus and other haemolytic streptococci including B, C and G. Gram-negative rods such as Escherichia coli are implicated in the elderly, immunosuppressed, or patients with comorbidities. Pseudomonas aeruginosa is implicated in intravenous (IV) drug users and patients post-surgery or intra-articular injections. Kingella kingae causes septic arthritis in children younger than four years of age. Neisseria gonorrhoeae, Neisseria meningitidis, and Salmonella species can also cause septic arthritis as part of a disseminated infection. Septic monoarthritis commonly occurs in patients with disseminated gonococcal infection. Blood cultures, white blood cell count, C reactive protein (CRP), electrolytes, and liver function tests are indicated. Serial CRP is useful in monitoring response to treatment. If there is a history of unprotected sexual intercourse, gonococcal testing is recommended. Brucella serology and Tropheryma whippei serology may be considered based on the clinical history. Joint fluid aspiration should be performed by a specialist within the hospital. Joint fluid aspirate is processed in the laboratory for microscopy, culture, and sensitivity. Gram stain can show an increase in neutrophils and presence of bacteria. The guidelines provided by the British Society for Rheumatology on the management of hot swollen joints in adults has provided advice for empirical treatment for suspected septic arthritis, but the local antibiotic policy should also be considered. Initial treatment is with intravenous flucloxacillin 2g four times daily, or 450– 600mg four times daily of intravenous clindamycin to cover S. aureus.