Book: pathogens Flashcards

Question

Which microorganism causes cholera?

Answer 1

Vibrio cholerae. Classical cholera is caused by V. cholerae 01, while most of the recent epidemics have been due to the El Tor biotype. Two variant strains of the El Tor biotype have developed, 0139 Bengal, restricted to Asia, and an El Tor producing toxin of the classical strain (ETEC).

Answer 2

A profound diarrhoea of rapid onset that leads to dehydration, and death should be considered as a case of cholera until proved otherwise. The diarrhoea contains no faecal particles but is watery and flecked with mucus (not cells), the so-called rice-water stools. The passage of large quantities of fluid and electrolytes leads to rapid and extreme dehydration, which can be fatal. Vomiting can also be present in the early stages. Blood group O is associated with more severe cholera.

Answer 3

V. cholerae can be identified from the diarrhoeal discharge, vomitus or by rectal swab. Its characteristic mobility (it vibrates, hence being called a vibrio) can be seen by dark ground or phase contrast microscopy and is inhibited by specific antiserum. Confirmation of the diagnosis is made by culture on TCBS (thiosulfate-citrate-bile salts-sucrose) agar. A suitable transport medium is Carey Blair, or alternatively 1% alkaline (pH 8.5) peptone water, which can also be used for water samples. A dipstick rapid diagnostic test is available.

Answer 4

Classical cholera is a disease of water transmission, whereas transmission of El Tor is by both water and food. Generally, epidemic cholera is transmitted by water, and endemic cholera by food. It may appear in a seasonal pattern, often in association with other causes of diarrhoea (Fig. 8.2). It is the endemic nature of El Tor and its persistence in the environment that has been responsible for its prodigious spread. For every clinical case of El Tor cholera there can be as many as 100 asymptomatic cases, explaining how epidemics spread from one region to another, but not how infection remains in the environment. One method may be the persistence of infection in the human population due to continuous personto-person transmission in a subclinical asymptomatic cycle. When a susceptible person enters the cycle, or there is an environmental or climatic change, a fresh epidemic starts. A natural cycle has now been established in an aquatic environment, with V. cholerae living in copepods, or in other zooplankton, as found in algal blooms. Vibrios are easily destroyed by sunlight, chemical action or competing bacteria; however, where these elements are not present, they can survive in fresh water for some time and in saline for at least a week. The level of salinity needs to be between 0.01 and 0.1%, as is found in estuarine or lagoon water. V. cholerae in this saline environment can be taken up by shellfish or fish, which then form an alternative method of infection when eaten uncooked. Rising sea levels and increase in water temperature due to climate change make cholera outbreaks developing from an estuarine environment more likely. The isolation of V. cholerae from river water has been an enigma because epidemiological investigations show this source of infection to be important, but bacteriologists have not isolated organisms in sufficient numbers. One possible explanation is the presence of non-agglutinable vibrios (alternatively known as non-cholera vibrios), which are closely related to V. cholerae, except that they do not agglutinate antisera. However if they are infected with a phage virus, this transfers a toxin gene, which if in sufficient numbers leads to an outbreak. It is this multiplication of vibrios during the wet season, many of which contain the toxigenic phage, that leads to an epidemic. V. cholerae has been found to remain viable in crude sewage for over a month and in sewage-contaminated soil for up to 10 days, thereby providing a possible source of infection to rivers or wells. It has been isolated from a number of foodstuffs, especially those with a pH of between 6 and 8, such as milk produce (e.g. ice cream), sugar solutions, meat extracts or articles of food preserved by salt. Uncooked fish and vegetables that have been washed or irrigated by sewage effluent have been responsible for outbreaks. Direct person-to-person spread, or via fomites such as utensils or drinking straws (in home-brewed alcohol parties), do not appear to be as important as expected. Even in persons attending the death of a cholera case, it is more likely that infection will result from drinking water or consuming food that has been prepared for the mourning ceremony, rather than from the dead person or their shrouds. A case of cholera can excrete between 10 7 and 10 9 V. cholerae/ml of diarrhoeal discharge, and as the volume of this discharge may be in excess of 20 l/day, the potential for contamination of the environment is enormous. Clearly though, the severe case is unlikely to be anything but a transitory source; it is the asymptomatic case passing 10 2–10 5 organisms/g of stool in a spasmodic manner that poses the greatest hazard. A high dose of V. cholerae is required to infect the healthy subject. Some 10 6–10 8 organisms are needed, but if the person has a decreased gastric acidity, then 10 3 organisms may be sufficient. Lowered gastric acidity is found more commonly than expected and may be related to malnutrition or diet. Cannabis smoking is also known to depress gastric acidity.

Answer 5

Carriers are of short duration. Seventy per cent of cholera cases are free of vibrios at the end of the first week and 98% by the end of the third. Long-term carriers are rare and of no epidemiological importance.

Answer 6

Humans are the only known reservoir, but the persistence of the organism in the environment, in association with a toxigenic phage, as discussed above, may be another source. In endemic areas cholera is a disease of children (adults having developed immunity in childhood), whereas in its epidemic form adults are the more usual victims. The disease is associated with poverty and poor hygienic practices. Classical cholera is restricted to South Asia and caused by V. cholerae 01. The El Tor biotype has infected Asia, Africa, Europe, Pacific Islands and South America, while the majority of cases are now found in Africa (Fig. 8.3). First isolated from pilgrims to Mecca in the quarantine station of El Tor in West Sinai (now Egypt) in 1906, it differs from the classical variety by producing a soluble haemolysin. It is classified as either Ogawa, Inaba or Hikojima of the classical serotypes. The importance of the El Tor biotype is that it can survive longer in water, is more infectious, can cause mild infections and more frequently produces the carrier state. These characteristics have all assisted in the extensive spread of this organism. The more virulent El Tor V. cholerae 0139 has been responsible for epidemics in India, Bangladesh, Myanmar, Thailand and Malaysia, but is fortunately now on the decline. In 1992, a variant of the El Tor biotype but with toxigenic effects similar to those of classical cholera (ETEC) appeared in Asia and has now replaced the original El Tor strain in many parts of Asia and Africa. Antibiotic-resistant strains are appearing but proper management of cases should not require the use of antibiotics.

Answer 7

Control is aimed at the cause. All too often a panic situation develops, foods are banned, vaccination given and quarantine instigated. If cholera is epidemic and preliminary investigations indicate that water is the vehicle of transmission, then the supply should be sterilized by super-chlorination (adding two to three times the calculated amount of chlorine required for the volume of water) or everybody told to boil their water. Boiling water is unpopular as it uses vital firewood and monopolizes scarce cooking pots, and the water has a flat taste. However, there is no reason why water cannot be boiled at the same time as the meal is cooked and simple clay pots used instead of metal ones. Boiled water can be re-aerated by shaking it up. A not so safe, but easier, method is to leave water to stand and then decant off the supernatant. A simple way of doing this is the three-pot system (Fig. 3.6). The SODIS method using polythene bottles of water heated by the sun can also be used. Chlorine can be added to a well or communal water supply, but any vegetable matter in the water will inactivate chlorine, and several times the amount calculated may be required. The banning or restriction of food should only be made on good epidemiological evidence. If fish are properly cooked before being eaten, then they are unlikely to be a source. Disruption of a fish-eating practice may have dire consequences on other aspects of people’s health. It is more often the fisherman rather than the fish, or the farmers rather than their produce, that are the purveyors of cholera. Quarantine is rarely effective, as bribery or evasion of the barricades by the few who might be carrying the infection negates the hardships borne by the many who are not. Giving tetracycline to immediate contacts of cases will reduce the number of asymptomatic carriers, but the widespread distribution of the drug will encourage tetracycline resistance. The original inactivated V. cholerae vaccination gives about 50% protection and only lasts for 6 months. It does not prevent the asymptomatic disease state and can actively encourage the spread of infection, so is not recommended as a method of control. Dukoral (WC/rBS) cholera vaccine consists of killed whole V. cholerae 01 in combination with a recombinant B subunit of cholera toxin. It confers protection of up to 90% for 6 months and has been found to be effective in preventing cholera in high-risk areas such as refugee camps and urban slums. Protection has been found to remain at about 60% for at least 2 years in adults and older children but declines rapidly in young children after 6 months. The vaccine is administered to adults and children over 6 years in two oral doses given 7 days apart. Children aged 2–5 years should have three doses, each given 7 days apart. A booster dose to adults and children over 6 years can be given after 2 years. The vaccine has been found to be safe when given to pregnant women and those with HIV infection. Dukoral can be used pre-emptively in high-risk areas, in epidemic situations and to protect travellers entering areas of high endemicity. Several mass vaccination campaigns have demonstrated its value in protecting populations at risk in an ongoing epidemic and in crisis situations where an outbreak of cholera has a high likelihood of occurring. It has also been found effective against ETEC. Two other vaccines, Shanchol and mORCVAX, are based on serogroups 01 and 0139, but do not contain bacterial toxin B subunits so are not effective against ETEC. Shancol is produced in India for internal and international use, while mORCVAX is used only in Vietnam. Shancol can be given to those over 1 year old and is administered in two oral doses given 14 days apart. These vaccines have been found to be as effective as Dukoral where ETEC cholera is not involved, providing longer-term protection to children under 5 years of age, as well as being cheaper. All these vaccines provide herd immunity, which is especially valuable in protecting young children. In high-risk areas, children as young as 1 year old should be targeted with Shancol or mORCVAX and 2 years olds with Dukoral, in periodic mass vaccination campaigns. Follow-up should be provided to give the second dose (and third with Dukoral) at 6 months. Booster doses should be given every 2 years. Pregnant women and HIV-positive persons should also be vaccinated. In epidemic situations, oral cholera vaccines can be administered to populations in high-risk areas, but this is only a short-term option. Reliance should not be placed on vaccination to control an epidemic, but other methods of control such as sterilizing water supplies should mainly be used. Persons dying from cholera should be buried promptly and the ceremony kept to a minimum. Disinfectants and hand-washing facilities should be provided at treatment centres and when bodies are prepared for burial. Flies should be controlled by disposing of or covering all faecal discharges, although they have not been shown to play a significant role in transmission

Answer 8

The vibrio binds to the cells and produces an enterotoxin, which activates adenyl cyclase, an intracellular enzyme that initiates a system of fluid and ion transport from the plasma to the intestinal lumen. This strategy is used by the vibrio to flush out other bacteria that normally live in the intestine and compete with it. There is no mucosal damage and increased permeability is unlikely, which explains why glucose and electrolytes can still be absorbed by the mucosa. This allows large quantities of low-protein fluid, bicarbonate and potassium to escape through an essentially undamaged intestine. Management is to correct dehydration in this otherwise self-limiting disease. Fluid replacement must be rapid and adequate, the most easily available being the first choice. If rehydration can be started as soon as cholera symptoms begin, then oral rehydration will be all that is required. ORS can either be prepared from ready-mixed packets of salts (Section 8.1) or by making a sugar and salt solution (Fig. 8.1). Unfortunately, most cases have already lost a considerable quantity of body fluid on presentation, which means that they will require intravenous infusion. If available, Ringer-lactate solution (Hartmann’s) contains the nearest approximation of electrolytes to that being passed in the diarrhoeal fluid. As a second best, a mixture of two units of normal saline and one of sodium bicarbonate can be used. The patient should be rehydrated intravenously as rapidly as possible, then oral rehydration solution substituted once the patient can swallow. This allows the body mechanisms to regulate electrolytes, as ionic imbalance can rapidly occur with intravenous infusion – from which many patients succumb. The body fluid deficit should be restored, followed by maintenance of one and a half times the equivalent amount of bowel loss. Fluid loss can be measured into a bucket under the bed. A bed or cholera cot is not essential though, and the patient can be nursed on a plastic sheet laid on the ground with the earth hollowed out under the pelvis to take a receptacle to collect the outpouring fluid. Tetracycline is not essential in treatment, but shortens the duration of the illness and quantity of fluid replacement required. Tetracycline is given in a dose of 500 mg 6 hourly for 3 days, or doxycycline in a single dose of 300 mg. Sensitivity must be monitored as the development of tetracycline resistance will necessitate changing to another antibiotic. The management of a cholera epidemic requires speed and good organization. Essentially, treatment is taken to the people by setting up treatment centres at strategic places in the vicinity of the epidemic. These can be dispensaries, schools, church halls or even tents that are supplied with staff and fluids. Cholera patients do not need to be treated in hospital.

Answer 9

Surveillance for cholera is both national and international. Under the International Health Regulations (2005) any outbreak is a health event of international concern so should be reported to the World Health Organization (WHO). This will provide an advance warning system to other countries, but neighbouring countries should be notified directly. Cases should be reported using the WHO case definition and not just laboratory-confirmed cases. Nationally, a warning system can be implemented for diarrhoeal diseases where an increase in numbers, or in persons dying from diarrhoea, may indicate an underlying outbreak of cholera (Fig. 8.2). There is considerable concern that V. cholerae 0139 has the potential to cause a pandemic, so this serogroup should be tested for. Where cholera exhibits a seasonal pattern, then the population and health staff can be placed on the alert when the next season starts.

Answer 10

Infectious hepatitis is a viral infection caused by hepatitis A virus (HAV).

Answer 11

The main pathology is inflammation, infiltration and necrosis of the liver, resulting in biliary stasis and jaundice. The infection generally starts insidiously; the person feels lethargic, anorexic and depressed. Fever, vomiting, diarrhoea and abdominal discomfort ensue, with the passing of pale-coloured stools, before the appearance of jaundice reveals the diagnosis. Once jaundice appears, the person generally starts to feel better. Hepatitis A is a mild disease leading to spontaneous cure in the large majority, with only a few cases developing acute fulminant hepatitis and, even more rarely, severe chronic liver damage. There is an increase in symptomatic and severe cases with increasing age, while children may be virtually asymptomatic

Answer 12

Diagnosis is made on clinical grounds and by the demonstration of IgM antibodies to HAV (IgM anti-HAV) in serum. When the symptoms are jaundice, the disease is determined by looking at clinical indicators (fever, lethargy, abdominal discomfort for hepA) and occurrence (worldwide, epidemic in institutions for hepA)

Answer 13

The early case is highly infectious, contaminating food and water. Infection can also be transmitted directly from poor personal hygiene, such as by handshaking. Intrafamilial transmission is the commonest pattern, generally due to contamination of food and utensils by a food handler, but large epidemics can occur where a person in the early stages of the illness prepares communal food. Because of its insidious nature, the disease is not generally recognized until jaundice appears, by which time infection may have been widely transmitted. Hepatitis is mainly a disease of poor sanitation, with water and food as the principal vehicles of transmission, but it can also occur when sanitation is good. Salads, cold meats and raw seafood are common vehicles of transmission. The carrier state is not important, but a large number of asymptomatic cases are produced. Epidemics occur when sewage contaminates water supplies, producing infection in people who have previously acquired some immunity, suggesting that the disease may be dose dependent. Where there is a large infecting inoculum, then infection can occur despite previous experience of the disease. Chimpanzees and other animals have been found infected, but probably have no epidemiological significance.

Answer 14

Hepatitis is endemic in most tropical countries, children coming into contact with it early in life and developing a degree of immunity. Non-immune persons, such as those from an area of good sanitation, coming into this environment are likely to develop the disease. Epidemics occur in developed countries, especially in institutions such as schools and prisons, owing to poor food hygiene.

Answer 15

During an outbreak of hepatitis A, extra effort should be made to encourage scrupulous personal hygiene with hand washing. Anybody who starts to feel unwell should be temporarily relieved of preparing food. In an epidemic situation, a search should be made for the origin of the outbreak and preventive measures taken. In the long term, water supplies and sanitation should be upgraded. Hepatitis A vaccine protects the individual at risk, and should be mandatory for those going from an area of good sanitation to one of poor sanitation, such as tourists and expatriates. Two doses are required given 6–18 months apart, although one dose still gives high levels of immunity. Immunity from a two-dose regime may be lifelong, but a booster at 10 years is currently recommended. As most of the population in an endemic area will have met the infection as children and either had no symptoms or just a mild infection, there is no case for mass vaccination, except for high-risk groups. Some countries in the Americas now include hepatitis A in the routine childhood vaccination programme.

Answer 16

There is no specific treatment for hepA and supportive measures should be undertaken. Fatty foods should be avoided and a good fluid intake maintained.

Answer 17

``` Once hepatitis (A) has been detected, health authorities should notify central authorities and surrounding areas. ```

Answer 18

Parasites. Taenia saginata, the beef tapeworm, and Taenia solium, the pork tapeworm.

Answer 19

The adult worm of both species can live in the intestines, producing little pathology, being diagnosed often by accident. It does, however, share the food supply of its host so that debility can occur. The serious problems are due to the Cysticercus cellulosae (from T. solium). The cysticerci die and calcify, those in the brain being a common cause of epilepsy or mental disorder. Gastric disturbances can occur, often with mild pain, or the patient may notice the proglottids being discharged. If people are unfortunate enough to be infected with cysticercosis, they may suffer from convulsions, intracranial hypertension (vomiting, violent headaches and visual disturbances) or psychiatric disorders (confusion, apathy or dementia), there being a 50% mortality in untreated cases.

Answer 20

Diagnosis of beef and pork tapeworms is made by finding the proglottids in the faeces, with patients often making their own diagnosis. It is very important to distinguish between T. saginata and T. solium in view of the danger of inducing cysticercosis: T. saginata has 18–30 compound branches of the uterus on each side, whereas T. solium has only 8–12 (Fig. 9.6).

Answer 21

The adult worm lives in the small intestine of humans and as it matures gravid segments break off and are passed in the faeces. Cattle or pigs inadvertently eat the proglottids (the mature segments), or the discharged eggs contaminate the pasture. Alternatively, the animal can become infected by drinking water polluted by sewage. It has also been found that birds feeding on sewage can carry eggs long distances and then deposit them on pastureland. Flies might have a place in transmission as well. The eggs develop into cysticerci in the muscles, favouring the jaw, heart, diaphragm, shoulder and oesophagus. Humans acquire the disease by eating improperly cooked beef or pork containing the cysticercus. The beef tapeworm (T. saginata) and the pork tapeworm (T. solium) have the same life cycle except that the intermediate stage, the cysticercus of T. solium, can also occur in humans. This happens by swallowing eggs directly, either by autoinfection from eggs in food or water, or through sewage contamination. Also, any gastric disturbance that might cause the regurgitation of proglottids into the stomach (including improper treatment) can lead to the liberation of vast quantities of eggs, with the result that cysticerci are produced anywhere in the body, including the brain, orbit and muscle.

Answer 22

Beef and tapeworms are the commonest and most cosmopolitan of all the tapeworms, with a worldwide distribution in beef- and pork-eating areas, especially in the tropical belt and Eastern Europe. Over 60 million people are thought to be infected. In such areas of beef and pork eating, there is a ready transmission cycle in operation. Finding the worm in humans means that transmission is probably reasonably common in that area, whereas in other places where beef and pork eating are just as much part of the usual diet, but food hygiene is adequate, they are not found. T. saginata is increasing in Europe, probably because of human sewage contamination of animal drinking water. T. solium is common in Mexico, Chile, Africa, India, Indonesia and Russia.

Answer 23

The main means of controlling beef and pork tapeworms is the proper cooking of meat. The underdone steak or joint of meat where internal temperatures are not high enough to kill the cysticercus are common ways in which transmission can still take place, despite cooking. Proper control of slaughtering in official abattoirs, with meat inspection, can prevent the dissemination of infected meat. Condemned carcasses must be burnt

Answer 24

The treatment for both beef and pork tapeworms is with niclosamide 2 g as a single dose. Alternatively, praziquantel as a single dose of 5–10 mg/kg can be given. Praziquantel at a dose of 50 mg/kg for 15 days can be used for cerebral cysticercosis in conjunction with corticosteroids, as an inpatient.

Answer 25

Where a localized cycle of infection of beef and/or pork tapeworms is occurring, investigation may reveal a sewage leak or other source of contamination that could easily be rectified.

Answer 26

Parasites. Ancylostoma duodenale and Necator americanus cause the two common hookworm infections of humans.

Answer 27

The infective (filariform) larvae directly penetrate the skin and migrate to a blood or lymphatic vessel, where they are carried in the circulation to the lungs. Here they break out of the alveoli, find their way up the trachea and enter the gastrointestinal tract. The adult stage is finally reached in the duodenum or jejunum, where the male and female worms mate and produce eggs. Despite its extensive journey through the human body, like Ascaris, the hookworms are very well adapted to their host and only produce symptoms when heavy infections occur. The passage through the skin can result in a transient urticaria (ground itch), while that through the lungs can cause pneumonitis and haemoptysis. Occasionally, the haemoptysis can be sufficient to suggest a diagnosis of tuberculosis. The main effect results from the adult worms attaching to the intestinal wall, where they invaginate a piece of mucosa and extract blood and nutrients. Anaemia results from continued blood loss and depletion of iron reserves. The degree of anaemia produced depends on the worm load, and one estimate calculates that 60–120 worms (measured by 30 worms excreting 1000 eggs/g faeces) will result in slight anaemia, whereas over 300 worms (10,000 eggs/g faeces) will cause severe anaemia. The newly established worm may produce several bleeding points, and if the sexes are unbalanced the search for a mate can result in increased activity. These effects will naturally be most profound in the growing child and the pregnant woman. It is the combination of malaria, malnutrition and other intercurrent infections with hookworms that accentuates the seriousness of this infection. On the plus side, recent research suggests that low-level infections may have a protective effect from the child developing asthma, inflammatory bowel disorders and even diabetes type 1. So long has the parasite been in association with humans that the anti-inflammatory substances secreted by the worms are used to desensitize the body. So a few worms may be an advantage.

Answer 28

Hookworm eggs are found in faecal examination. They are oval and have colourless thin walls that differentiate them from Ascaris, which has a thick brown exterior. The eggs of the two hookworm species are identical and only the adults can be differentiated, mainly from their characteristic mouthparts. A polymerase chain reaction (PCR) method of identification can be a useful additional aid.

Answer 29

The eggs are passed in the faeces and hatch within 24–48 h to liberate an intermediate (rhabditiform) larva. After some days, it moults to produce the infective filariform larva. In suitable conditions of moist, warm but shaded soil (30°C for N. americanus and 25°C for A. duodenale), this stage of the larva can live for several months, awaiting the opportunity to penetrate through the skin of a new host. (The ingested third-stage larvae of Ancylostoma can also produce infection.) The larva commonly penetrates the foot of the unshod person and intense infection can occur where areas of beach or bush are demarcated for defecation purposes. Non-human hookworms can also penetrate the skin and produce cutaneous larva migrans. Young infants can have very high infections due to larvae in the mothers’ breast milk. Hormonal change during pregnancy causes a migration of dormant hookworms, many of which reach the mammary glands.

Answer 30

N. americanus, despite its name, is the more widely distributed, being found extensively throughout the tropical belt and well north of the tropic of Cancer in America and the Far East. A. duodenale is found in the Far East, the Mediterranean and the Andean part of South America (Fig. 10.3). It has been suggested that N. americanus was carried from Africa to the Americas as a result of the slave trade. Altogether, some 740 million of the world population have hookworms.

Answer 31

Control and prevention is of hookworms by use of pit latrines or other methods of sanitation. The wearing of footwear effectively prevents penetration by the larvae. The open sandal type of footwear often worn (thongs, flip-flops) is not effective and infection can readily occur. Mass treatment can be given to reduce the parasite load, but without health education and the proper use of latrines this will only produce a temporary improvement.

Answer 32

A number of drugs are effective in treatment of hookworms: albendazole 400 mg single dose, mebendazole 500 mg single dose or 100 mg twice a day for 3 days; levamisole 2.5 mg/kg daily for 3 days; oxantel 10 mg/kg daily for 3 days; or pyrantel pamoate 10 mg/kg daily for 3 days. The treatment should be repeated 12 weeks after the original course of treatment. There is concern that resistance could develop, as has happened in veterinary practice, so combinations such as mebendazole plus levamisole or pyrantel plus oxantel have been advocated. In the debilitated child, supportive therapy will need to accompany deworming. Iron supplementation, or in the severe case blood transfusion, will be required to treat the anaemia. In the treatment of filariasis and onchocerciasis, a combination of albendazole plus ivermectin or albendazole plus diethylcarbamazine are used (see Sections 15.7 and 15.8), so treatment of helminths often occurs as an extra benefit. The albendazole plus ivermectin combination is more effective for Ascaris and Trichuris.

Answer 33

When mass treatment is planned, an initial survey will delineate the size of the problem. Follow-up spot checks of individual stool specimens can be made to assess progress.

Answer 34

The main parasites are Schistosoma haematobium, S. mansoni and S. japonicum. Other species, such as S. intercalatum and S. mekongi, do occur, but they are only important in well-defined areas and their epidemiology and control are similar to those of one of the three main types.

Answer 35

Infection normally starts in childhood, often with very few signs of the disease until adulthood. Passing blood in the urine is one of the first signs of S. haematobium disease, but because it is so common in the local area it is generally ignored; boys thinking it quite normal that they should have period bleeding like girls do. Infection and egg output increases up to about 15 years of age and then declines; individuals vary in their response, some persons acquiring heavy infections and developing severe pathological changes, while others have only minor symptoms. The more serious manifestations are liver fibrosis, portal hypertension and obstructive urinary problems, the pathology depending upon the species of parasite and the number of eggs deposited in the tissues; S. mansoni and S. japonicum infections lead to intestinal and liver damage, while S. haematobium infection leads to bladder complications, including bladder cancer.

Answer 36

Diagnosis of schistosomiasis is made by finding the characteristic eggs (Fig. 9.1), in S. haematobium in the urine, and in S. mansoni and S. japonicum in the faeces or from a rectal snip. Urine samples are best collected between 11.00 and 15.00 h, when egg output is at a maximum. Leaving the urine to stand, centrifuging it, or passing it through a filter increases the chance of finding eggs. While qualitative diagnosis is required in the individual case, quantitative estimates are more valuable in epidemiological investigations. In S. haematobium, the simplest method is to pass 10 ml of urine through a filter in a Millipore holder. The paper or membrane is taken out, dried and stained with ninhydrin and the eggs counted directly. Immunological methods, immunofluorescence antibody test (IFAT) and enzyme-linked immunosorbent assay (ELISA), have also been developed for schistosomiasis, but they only indicate recent or past infection, so eggs must be looked for to confirm the diagnosis. However, these tests are useful in epidemiological surveys for rapidly defining the extent of the infected area. Pathology is related to the number of worms, which can be measured by the number of eggs produced. In S. haematobium, the production of 50 eggs/ml of urine or above is regarded as the level of severe pathology and much of presentday control strategy is aimed at reducing the egg count to below this level.

Answer 37

Infection results from cercariae directly piercing the skin of a person when they go into the water. On penetrating the subcutaneous layer of the host, the cercaria becomes a schistosomule, migrates to the lungs and finally develops into an adult in the portal vessels of the liver. Both male and female worms are required, so pairing takes place prior to migration to the final destination in the mesenteric or vesical plexus. Adult worms can live 20–30 years, but are active egg producers for 3–8 years, although some have produced viable eggs for over 30 years. The egg output/day in S. haematobium is some 20–250, in S. mansoni 100–300 and in S. japonicum 1500–3500. It is this massive output of eggs in S. japonicum that leads to the more rapidly developing and severe pathology of infection with this parasite. Less than 50% of eggs manage to pass through the bladder or intestinal wall to develop further, the remainder being trapped in the tissue. On reaching water, a temperature of 10–30°C and the presence of light induce hatching. Miracidia actively search out a snail using geotactic and phototactic behaviour, homing in on a chemical substance ‘miraxone’, inadvertently liberated by the snail. The miracidium must penetrate a snail within 8–12 h, their chance of success decreasing with age. Some 40% of snails are infected at a distance of 5 m in still water, but where the water is moving, similar infection rates can occur at a far greater distance. Normally, infection occurs in water flowing at 10 cm/s or less. Even after the rigours of the journey, when miracidia have entered the correct species of snail, many are inactivated and only a small proportion develop into sporocysts. This is determined by the part of the snail entered and immunity to reinfection developed by the snail. Cercariae are stimulated by light to emerge from the snail when the ambient temperature is between 10 and 30°C. Cercarial emergence increases as daylight penetrates the watery environment, producing a peak for S. mansoni at 12 noon and for S. haematobium in the mid-to-late afternoon. With S. japonicum, the stimulus produced by light is delayed and maximal cercarial liberation occurs at 23.00 h. The number of cercariae issuing from a snail can be immense, in the order of 1000–3000/day, but this depends upon the species and relative size of the snail. Where more than one miracidium has penetrated a snail, there is depression of cercarial production; this may also occur if the snail is host to other trematode infections. Cercarial output is greatest in S. mansoni, less in S. haematobium and least of all in S. japonicum. Cercariae survive for 24 h, but their greatest chance of penetrating the host is when they are young. When cercariae enter within 2 h of release, only 30% die, but this rises to 50% at 8 h and 85% at 24 h. The snail intermediate hosts are species specific, Bulinus spp. in S. haematobium, Biomphalaria spp. in S. mansoni and Oncomelania spp. in S. japonicum. They are illustrated in Fig. 11.1. They can adapt to a wide range of habitats, from natural waterways to temporary ponds and cultivated rice fields. Whenever there is sufficient organic matter on which to feed, snails will be found. Within a body of water, distribution may be quite irregular, with dense colonies in some places and complete absence in others. Various factors which may influence snail colonization, are: • Electrolyte concentration. Snails demand a minimum calcium concentration, and cannot tolerate high salt content or a low pH. • Light is not required by the snail, and they can often survive in near total darkness. • Rainfall may herald the end of the dry season and provide water in which snail populations can increase, but if the rainfall is too heavy it may flush out the snails, resulting in a subsequent decrease. Snail populations may therefore follow a seasonal pattern. • Temperature rise encourages expansion of the population up to a maximum of approximately 30°C. • Density is a limiting factor and results in reduced growth. • Aestivation or the ability of snails to survive out of the water for weeks or months allows populations of snails to continue from one season to another, possibly also transferring immature infections of S. haematobium and S. mansoni. The snail host of S. japonicum can survive conditions of desiccation best of all. Snails are capable of self-fertilization, although cross-fertilization is more common. Their reproductive capacity is phenomenal and a single snail can produce a colony within 40 days and be infective in 60. When conditions are optimal, many species of snails will double their population in 2–3 weeks. In measuring the age of snail populations, size of snails is a useful indicator. A large number of small samples from several different areas are preferable to a few large samples in estimating the numbers and density in watercourses. Infection rates in snails are generally low, only some 1–2% of the colony being infective, but even so, this level is sufficient to account for high prevalence rates in the human population. Humans contaminate water either by urinating or defecating into or near watercourses. Egg output is variable between individuals and at different times in their lives; a few individuals have heavy infections and egg outputs, while the majority have light infections. In areas of high endemicity, children between 5 and 14 years are responsible for over 50% of the contamination. As the infection rate declines, then older age groups become more important. People are infected by collecting water, washing (both clothes and the person), in their occupations (such as fishing) or during recreation. Children are most commonly infected when they play in the water, while in adults it is when they carry out their domestic duties or occupations. Infection is generally due to repeated water contact over a long period, but can occur from a single immersion if it coincides with a large number of cercariae in the water. Animals such as water buffalo, cattle, pigs, dogs, cats and horses can also serve as reservoirs of S. japonicum, but they are less important than humans as sources of infection.

Answer 38

S. haematobium and S. mansoni were originally diseases of Africa, where they were widely distributed, but with the massive exodus of slaves that took place in the 17th and 18th centuries this legacy was carried with them. The East African slave trade carried S. mansoni to the Arabian peninsula, and S. haematobium to the Yemen and Iraq. The Western trade was solely in S. mansoni, which found a suitable snail host in South America and the Caribbean. S. japonicum probably originated in China, where it has been discovered in mummified bodies, but is also found in the Philippines, Taiwan and Sulawesi in Indonesia (Fig. 11.2). No cases have been found in Japan since 1978. A separate species, S. intercalatum, pathogenically similar to S. mansoni, is found in the Congo, Cameroon, Central African Republic (CAR), Chad, Gabon and São Tomé. S. mekongi is restricted to the Mekong River basin in Laos, Thailand and Cambodia. Other localized species are Schistosoma malayensis in Peninsular Malaysia and Schistosoma mattheei in southern Africa. Climate change is likely to reduce the areas where S. mansoni is prevalent due to it becoming too hot for the snail host to breed. However, in areas where the snail is reduced by a cooler temperature, such as in southern Africa, increased warming could increase its endemicity.

Answer 39

Control, prevention and treatment. There are two approaches to the control of schistosomiasis: • Reduce the transmission of the parasite. • Reduce the level of infection in individuals. The first attempts to control the parasite, while the second aims at minimizing the pathological effects. The various methods of control are: Reduce contamination of the environment. Humans pollute the environment by urinating or defecating into bodies of water. This can be minimized by encouraging the use of latrines. Unfortunately, it is very difficult to get everybody in a family or community to always use a latrine and the few non-users will be sufficient to maintain a level of pollution (see Section 2.4.2). There is also the longevity of the adult worms, meaning that prevalence rates will remain static in the community for a considerable length of time. Reduction of the snail intermediate host. The snail is a vulnerable link in the life cycle of the parasite and can be attacked in an effort to break transmission. The various methods that can be used are: • predators; • biological control; • water management and engineering; and • molluscicides. Various kinds of fish (Tilapia and Gambusia particularly) are natural predators, but they will only reduce snails to a certain level unless they have an additional source of food when there are few snails left. Snails, especially of the Marisa and Helisoma genera, compete for food supplies and Marisa will even prey on eggs and juveniles of Biomphalaria. Another approach to biological control is the sterile male technique, but as many snails are hermaphrodite, this is only suitable with Oncomelania. Where foci of infection consist of small and temporary ponds, these can be drained or filled (by controlled tipping of household refuse). Where canals and irrigation systems are responsible, then a concrete lining, increasing the rate of flow and any method to reduce vegetation can discourage snail habitation. Unfortunately, these methods are rarely effective on their own and need to be combined with a molluscicide, niclosamide (Bayluscide), which can be administered as a liquid, which is suitable for treating moving water, or as granules in lakes and ponds. Continuous application is required to have a sustained effect on the snail population. This method has the disadvantage of killing fish and is expensive. Cheaper preparations, such as copper sulfate, are still in limited use and naturally occurring plant preparations such as Endod (Phytolacca dodecandra) have shown promise. However, the remarkable recovery of snail populations once control methods are removed, and the cost of molluscicides, make snail reduction a less effective approach to schistosomiasis control. Reduction of water contact. Preventing water contact can be highly effective in the individual. Various ways of encouraging this are: • Health education, especially in schoolchildren, but this is often ineffective unless an alternative, e.g. swimming pool, is provided. • Providing places to wash has been disappointingly ineffective for the cost involved. • Where areas of absent or minimal transmission occur in occupational or recreational bodies of water, people can be encouraged to use these, rather than the heavily infected parts. • Wearing rubber boots when wading through water, or if accidental exposure occurs, then rubbing vigorously with a towel and applying 70% alcohol. • Drinking water can be treated with iodine or chlorine, or if left to stand for at least 48 h, cercarial die-off will be complete. Reduction of human infection by mass chemotherapy. Praziquantel single dose mass drug administration at 40 mg/kg is now the method of choice. A suitable target population is schoolchildren between 5 and 15 years of age, where mass therapy is used. Alternatively, only the positive cases, or those with heavy infections, are treated following a simple diagnostic procedure. Individual treatment, based on worm-load estimation, aims at disease control by reducing morbidity. It permits limited resources to be more widely spread and attempts the less ambitious target of disease reduction rather than transmission reduction. The antimalarial drug artemethur is also valuable in the control of schistosomiasis and could be used in areas where there is no malaria, such as China, southern Brazil and South-west Asia. It can be used in combination with praziquantel. Reduction of the animal reservoir. Animal reservoirs are responsible for maintaining S. japonicum. In order of importance, these are dogs, cows, pigs, rats and water buffalo. As most of these are domestic animals, proper animal management can reduce contamination of the environment. Vaccination of domestic animals could be used. Baboons and monkeys have been shown to be reservoirs of S. mansoni and could play a part in maintaining infection. There is little prospect of controlling these animals. Vaccination. There are difficulties in preparing a vaccine because the schistosome is able to absorb host antigen and mask its presence, but several vaccines are under trial. A 28 kD S. haematobium GST (glutathione Stransferase) vaccine is showing some promise, while S. mansoni antigens have also been tried, but no vaccine has shown more than partial protection. Another approach is to reduce egg production in female worms, with which some success has been achieved in S. japonicum. Strategies for schistosomiasis control. Various different approaches to the control of schistosomiasis have been tried depending on the resources and nature of the disease, as follows: • The raising of economic standards by the provision of water supplies, sanitation, environmental engineering and water management has been shown to be effective on a long-term basis in countries such as Japan and China. • In well-controlled irrigation schemes, mollusciciding on its own may be effective. Where discipline and motivation of the population are less certain, then a double approach of mass chemotherapy and reduction of water contact is more effective. • When resources are meagre and the greatest benefit for limited finance is required, then treatment of high worm load cases is the method of choice.

Answer 40

Effectiveness of control strategies can be measured by: • change in incidence rate; • a shift in peak prevalence to an older age group; • reduction in geometric mean egg output; and • greater awareness of socio-economic values, e.g. the use of water supplies and sanitation facilities.

Answer 41

Measles virus is a member of the Paramyxoviridae family of viruses.

Answer 42

Measles normally commences with a prodromal fever, cough, conjunctivitis and small spots (Koplik’s spots) most easily seen inside the mouth. The characteristic blotchy rash begins on the third to seventh day of the illness, generally on the face, but soon spreads to the whole body. In developing countries, measles is a serious disease and accounts for a considerable amount of mortality and morbidity in the childhood population. It has a particularly severe effect on the nutritional status of the child, so the healthy child will lose weight and the malnourished child will become critically ill. The peak of infection is between 1 and 2 years of age, at the very time when breast milk alone is an inadequate source of food and weaning foods may not yet have been introduced. The association of nutritional change and measles can be, and often is, a lethal combination. There are a number of reasons for the nutritional depletion produced by measles. Any disease process puts extra demands on the body, increasing catabolism. Fever and the desquamation of all epithelial surfaces demands protein replacement, which is handicapped by a sore mouth, often secondarily infected by Candida, preventing the child from sucking properly, so that even breast milk is not taken. Then from the other end, diarrhoea, which is such a common feature of measles in developing countries, discharges further the body reserves. But perhaps the greatest weight loss is due to immunosuppression, much of this taking place after the child has recovered from the acute attack. The disease process attacks all epithelial surfaces, producing most of its complications in the respiratory tract. Pneumonia is the commonest complication, while laryngotracheobronchitis is serious, with a high mortality. Acute respiratory infections (ARIs, see Section 13.2) are one of the leading causes of childhood ill health, and the sequelae of measles responsible for a large component of this problem. If the acute pneumonia does not kill, the damage done makes the child more susceptible to further attacks of respiratory infection when the measles has long gone. The effects on the eye can cause blindness. Corneal lesions result from epithelial damage, which can lead to ulceration, secondary infection and scarring. In severe cases, perforation or total disorganization of the eye can occur. These severe effects only result if there is concomitant Vitamin A deficiency, so giving Vitamin A to all measles cases is effective. Measles, by its nutritional and direct effects, has been regarded as the most important cause of blindness in a number of tropical countries. Measles is an important cause of otitis media. It can also result in encephalitis, either the acute form or a late slow-onset sclerosing panencephalitis, which is always fatal.

Answer 43

Measles is diagnosed on clinical criteria, but measles IgM can be found in the saliva with immunological tests.

Answer 44

Although the main feature of measles is the skin rash, it is transmitted by the airborne route, from nasal and pharyngeal secretions. This can be by articles contaminated with secretions, such as cloth or clothing used to wipe a running nose, as well as by respiratory droplets produced in a coughing bout. Virus can remain active in droplets in the air or on surfaces for up to 2 h. Measles is the most contagious of all infectious diseases and no age is spared. In the Fijian outbreak in the 1870s, adults as well as children succumbed, so that whole families were affected at the same time, deprivation and starvation resulting in a high death rate. Now that adults have experienced measles as children, the age of infection is getting younger. This is explained by greater contact of communities due to improvement of communication, while the intense social contact at a very young age (babies carried on their mothers’ backs) gives maximum opportunity for early transmissions.

Answer 45

Measles has been a severe infection in Western countries for a considerable period, producing mortality in poor and slum populations similar to that now seen in developing countries. Introduced with European exploration, it caused devastating epidemics, particularly in island communities, some of which never recovered their former population numbers. However, in many developing countries, in which it is a major problem, there is evidence that measles has been present for several 100 years, the pattern having changed from sporadic epidemics with all ages involved to one of endemicity in which the under 5 year olds are predominantly affected.

Answer 46

Control and Prevention of measles is by vaccination. As measles is such an infectious disease, it can be reckoned that every child will develop it. Some 10% will either have such a mild infection or be partially protected by maternal antibodies as to appear not to have been infected. A further 10–20% will not have measles until the following year owing to the epidemic effect, so the expected number of cases of measles can be calculated from the birth rate minus 25%. If the birth rate in a developing country is 50/1000, then 75% of this means that 37.5 cases of measles/1000 can be expected each year, which represents 37,500 cases in an administrative unit of a million people. Calculations like these can be used to estimate the number of children to be vaccinated and hence the vaccine requirements. At least 80% of susceptibles will need to be vaccinated to produce control of the disease, but a lower target may be acceptable in more isolated communities. This target will need to be achieved every year in rural areas, but as much as every 6 months in urban areas. Measles vaccine is 90% effective if the cold chain is not broken. Maternal antibodies protect the newborn infant for the first 6 months of life, but thereafter the child becomes readily susceptible to infection, with a peak around 1 year. The seroconversion rate is some 76% at age 6 months, 88% at 9 months and 100% at 12 months. Giving measles vaccination at 1 year would produce the best conversion, but by that time in developing countries some 50% will already have had the disease. Giving it at 6 months will be before all but a few have had the disease, but the seroconversion rate is so poor that not many will be protected. The best compromise is a first vaccination at 9 months, with a second vaccination at 12–18 months. In conditions of high infectivity, such as during an epidemic, admission to hospital or in a refugee camp, or in areas of high HIV prevalence (or if the infant has HIV), then reducing the age of vaccination to 6 months is justified. In this case, two further vaccinations should be given, the second between 12 and 15 months. In developed countries, vaccination is given at 12–13 months so the time taken to reduce the incidence in the population will be less, as shown in Fig. 12.1. The greater the coverage, the more rapidly this is achieved. For example, 60% coverage will theoretically take 12 years to reduce the incidence to zero if vaccination is given at 12 months, but will never be achieved with vaccination at 9 months. However, 70% coverage will achieve zero incidence with vaccination given at 9 months; this is being achieved by an increasing number of developing countries. Effective measles vaccination coverage will not only reduce the number of children developing the disease in an epidemic, but will have the secondary benefit of raising the age of developing the disease, as can be seen in Fig. 12.2. Epidemics had occurred in the Namanyere area of Tanzania regularly every second year until 1978, when there was only a minor increase, the main epidemic being delayed until 1979. This meant that children born in 1977 who could have expected to become infected in their second year of life (1978) had their measles put off until 1979, when they were beyond the age of maximum mortality. The chances of a susceptible child developing measles when admitted to hospital are very high as he or she is already sick with another complaint. It is fortunate that measles vaccine can produce protective immunity quicker than the wild virus (about 8 days for the vaccine and 10 for the disease), so as long as the child is vaccinated within 48 h of admission, he or she will be protected. Because of the severity of disease in the debilitated child, there are very few contraindications and the malnourished and those with minor infections should all be vaccinated. HIV infection is not a contraindication as the child is more likely to die from measles than from any complications of receiving a live vaccine. As vaccination coverage is increasing, a potential problem could arise because less maternal antibody is produced by mothers who have acquired their immunity from vaccination rather than by having measles. This means that infants of a younger age will become susceptible, so vaccination may need to be given earlier if coverage is not complete. Measles vaccine is conveniently combined with rubella (MR) or with both rubella and mumps (MMR) in countries intending to vaccinate against these diseases. Despite adverse publicity given to the MMR vaccine, no complications have been confirmed and the vaccine should continue to be used. However, MMR or MR should only be used in countries with a high vaccination coverage (over 80%) or else there is a danger of shifting the age of developing rubella, and hence congenital rubella syndrome (CRS), to women of childbearing age (see Section 12.3). Because of the effectiveness of measles vaccination, there is the very real hope that measles can be eliminated as a public health problem. A measles elimination programme has therefore been launched by WHO. On 29 April 2015, the WHO Region of the Americas was certified as having eradicated measles. This has been an incredible achievement and gives hope that similar action can eliminate this disease from other parts of the world.

Answer 47

There is no specific treatment for measles, but supportive therapy with fluids and easily digested foods needs to be given. Vitamin A supplementation should be given to all children with measles. Complications may require additional treatment, such as antibiotics for bacterial chest infections.

Answer 48

All cases of measles should be recorded and monthly totals charted to indicate epidemics and estimate when new epidemics will occur (Fig. 12.2). Measles has a seasonal pattern, which can vary markedly from country to country (Fig. 1.9), so this needs to be determined to work out the best time to supplement routine vaccination programmes. If measles cases are focal, then this may indicate gaps in vaccination coverage. As all children should be vaccinated, an estimate of vaccine coverage can be made by comparing the number of new vaccinations with the number of children born.

Answer 49

Mycobacterium leprae

Answer 50

Leprosy more dramatically than any other disease illustrates the conflict between the infecting organism and the host. M. leprae is widespread in the environment, yet only a small proportion of people ever show clinical symptoms of the disease, and the few that contact the disease respond in different ways to the challenge. The generation time from inoculation to multiplication of a stable number of M. leprae is only 18–24 days, but the development of the disease will take anything from 7 months to in excess of 7 years (mean 3–6 years). The first lesion is described as indeterminate (Fig. 12.3), because at this early stage it is impossible to decide to which place in the spectrum of disease it will develop. There is either a single, ill-defined, slightly hypopigmented macule, commonly seen on the face, trunk or exterior surfaces, or there may be a small anaesthetic patch. The lesion will then develop into a lepromatous or tuberculoid type, or oscillate in the transitional state of borderline leprosy between these two extremes. Lepromatous leprosy (LL) reflects the complete breakdown of the host’s immune responses and the maximum infection with M. leprae. In the early stages, signs of disease may be very few, but a skin smear will reveal large numbers of mycobacteria (multi-bacillary). Early signs that have been described but rarely observed are oedema of the legs and nasal symptoms of stuffiness, crust formation and bloodstained discharge. These are unlikely to be recognized as leprosy and it is generally not until the more obvious skin lesions become apparent that the diagnosis is made. Leprosy lesions favour the cooler parts of the body, so the buttocks, trunk, exposed limbs and face are the more likely sites. Lesions may be macules, papules or nodules, with or without a colour change, and often show lack of sweating when the patient becomes hot. The signs of nerve damage do not appear until much later in lepromatous leprosy, with a concurrent thickening of the skin of the forehead, loss of eyebrows and damage to the cartilage of the nose. The eyes are also attacked with an infiltrative keratitis, iritis and eventually blindness. Tuberculoid leprosy (TT) is at the opposite end of the spectrum, showing the full response of cell-mediated immunity to the attacking organism (Fig. 12.3). M. leprae has a predilection for nervous tissue and it is within this nervous tissue that the cell-mediated response takes place, causing early damage to the nerves. The tuberculoid patient therefore tends to present early with signs of weakness or loss of sensation. Palpation of the nerves will often demonstrate a thickening with loss of sensation or motor power in the distribution of the affected nerve. The ulnar nerve as it bends over the medial epicondyle at the elbow or the lateral popliteal nerve where it curves round the neck of the fibula are good places to palpate nerves for thickening. Dermal lesions are not raised, often appearing as apparently normal areas of skin, but lacking sensation or sweating when the patient exercises. Occasionally though, lesions are well defined and scaly with raised edges, but quite different from the succulent macules and papules of lepromatous leprosy. Loss of sensation should be demonstrated with a pin as well as with light touch. A skin smear in tuberculoid leprosy is nearly always free of bacilli (pauci-bacillary), so the diagnosis depends upon the detection of nerve damage. Borderline leprosy, as its name suggests, is on the border between the two extremes of lepromatous and tuberculoid leprosy. True borderline (BB) leprosy is uncommon, with the disease tending to progress to either the lepromatous (BL) or tuberculoid (BT) part of the spectrum. Signs therefore vary between the two extremes with features of each, but predominating in the features of one or the other. Borderline leprosy is common, but its instability leads to reaction and nerve damage, which can often be severe. Where the host response is adequate and cell-mediated immunity high, the disease tends towards the tuberculoid end of the spectrum; where response is low, the disease tends to lepromatous leprosy. Simultaneous HIV infection will shift the host response from tuberculoid towards lepromatous. Otherwise, the host response can vary over the course of the illness, producing reactions, which can either be upgrading (towards tuberculoid leprosy) or downgrading (towards the lepromatous). These are type 1 reactions. The nearer the case is to the centre of the spectrum, the more severe the reaction. Type 1 reactions may affect all tissues, or skin and nerves only, or produce a generalized systemic reaction. A different type of reaction (type 2) is found in lepromatous and borderline lepromatous cases and is associated with massive destruction of bacilli. Immune complexes are formed in the tissues and these lead to an increased reaction in existing lesions. The characteristic finding is erythema nodosum leprosum, which appears on the skin as painful red nodules, commonly on the face and exterior surfaces.

Answer 51

A skin smear is made from every suspected case of leprosy, collecting dermal tissue without drawing blood. A negative smear does not mean that a case is not leprosy, as tuberculoid cases rarely have mycobacteria. Smears are stained with Ziehl–Neelsen stain and the number of mycobacteria counted to give the bacillary index. 6+ Over 1000 bacilli in an average field 5+ 100–1000 bacilli in an average field 4+ 10–100 bacilli in an average field 3+ 1–10 bacilli in an average field 2+ 1–10 bacilli in 10 fields 1+ 1–10 bacilli in 100 fields Mycobacteria can also be obtained from nasal scrapings of the inferior turbinate. A skin biopsy is taken from tuberculoid and borderline patients, or a nerve biopsy where there is no skin lesion.

Answer 52

After a long period of uncertainty it has finally been shown that leprosy is transmitted via droplets from the nose and mouth during close and frequent contact. Large numbers of bacilli are found in the nasal discharges of lepromatous cases, and these are able to survive for 2–7 days outside the body. Individuals vary in their susceptibility and it is possible that repeated doses of bacilli, or a large infective dose, are required to produce disease.

Answer 53

Leprosy is found mainly in the tropical regions of the world, with poor socio-economic conditions probably a major factor. Lepromatous leprosy is more common in Asia and tuberculoid in Africa. This differing susceptibility might help to explain the response to BCG (Bacillus Calmette–Guérin) vaccination (see Section 13.1) in these two peoples. BCG given at birth can produce a hypersensitivity and change the cell-mediated immunity from negative to positive, but some people appear to have no natural immunity and remain always susceptible to the lepromatous form of the disease. BCG protected over 80% of schoolchildren in Uganda, but only 40% of children under 5 years of age in Myanmar. Leprosy can occur in an epidemic as well as an endemic pattern, but owing to the incredibly protracted life history of the disease, the epidemic form is rarely seen. Between 1921 and 1925 there was an epidemic on the Pacific island of Nauru; 30% of the population was infected and the disease was notably nonfocal. All ages were susceptible, with most people developing tuberculoid (BT– TT) leprosy, which healed spontaneously. It has been estimated that up to 5% of people are susceptible to lepromatous leprosy and contact with a lepromatous case increases the risk of infection. Children and young adults are more commonly affected, but the children of leprosy patients do not develop lepromatous leprosy any more frequently than the general population. It would seem that leprosy is very similar to tuberculosis (TB) in that the organism is more common than realized, asymptomatic infections may occur, but only those that are susceptible will develop the disease. Due to active control measures and multidrug therapy, there has been a marked reduction of leprosy in the world, with 180,000 new cases detected in 2012. Foci of high endemicity remain in Angola, Brazil, Central African Republic (CAR), Democratic Republic of Congo (DRC), India, Indonesia, Madagascar, Mozambique, Nepal and Tanzania.

Answer 54

The immediate control is a reduction of the leprosy reservoir by case finding, treatment and follow-up, especially of those with the lepromatous form of the disease. A small proportion of cases will present themselves, but an active search must be made for others, concentrating on selective groups. Schoolchildren should receive priority, as they are likely to contain a quarter of all cases and a higher proportion of new ones. Also, contacts of any case should be examined at frequent intervals, as leprosy is more common in those people that have prolonged contact with a leprosy case. All new cases are treated by multidrug therapy (see below). BCG vaccination induces hypersensitivity and increased resistance to developing leprosy in some ethnic groups, so is valuable in the prevention of leprosy as well as TB (Section 13.1). M. leprae-based vaccines are under trial in several countries, with promising results. The long-term reduction of disease will require an improvement in general hygiene, better housing and less overcrowding.

Answer 55

Treatment is determined by the bacillary index of the case. 1. High risk (multi-bacillary) LL and BL cases: a three-drug regime consisting of rifampicin 600 mg once a month supervised, dapsone 100 mg daily selfadministered, clofazamine 300 mg once a month supervised, then 50 mg daily self-administered. Treatment should be continued for a minimum of 12 months. 2. Non-bacillary cases, BT or TT: rifampicin 600 mg once a month supervised, plus dapsone 100 mg daily self-administered, for 6 months or six monthly doses within a 9 month period. 3. Non-bacillary single skin lesion: single dose of rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg. All patients with positive skin smears at the start of treatment should have repeat skin smears at 6 and 12 months. Clofazamine has the advantage of being anti-inflammatory as well as bacteriostatic, so can be used in the treatment of reactions at a dose of 100 mg three times a week. Steroids and thalidomide are useful in the treatment of reactions. Part of any leprosy programme is the development of a rehabilitation service. This not only encourages leprosy patients to present themselves for treatment, but also helps to return them as participating members of the community. Much can be done from limited resources, such as making sandals out of old tyres and pieces of wood. The elements of rehabilitation are to protect anaesthetic limbs, actively treat sores and ulcers, and provide support (including surgery) to restore function. The eyes are also damaged in leprosy and supportive treatment can do much to prevent blindness from developing.

Answer 56

. Dedicated leprosy fieldworkers have been found to be of considerable value in detecting new cases and following up cases under treatment, otherwise a system within the existing health service should be developed. Combining leprosy and TB surveillance is a useful economy. Initially, whole populations should be screened in areas of high endemicity, then concentration should be on examining schoolchildren and all contacts of cases. All cases should be registered, often managed as a combined programme with TB. Section 13.1 on TB follow-up and registration is equally applicable to both diseases.

Answer 57

Mycobacterium tuberculosis, but infection can also be caused by Mycobacterium bovis (from cattle) or Mycobacterium africanum. There are many mycobacteria occurring naturally in nature, including Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium scrofulaceum, that can sensitize the individual and interfere with the BCG (Bacillus Calmette–Guérin) vaccination against TB. In endemic countries, M. tuberculosis is widespread, and a quarter to a third of people in developing countries will develop the disease.

Answer 58

A productive cough with weight loss, fever and anaemia are the most important signs of TB. Any chronic cough persisting for 3 weeks or more, especially if there is also weight loss and anaemia, should be regarded as a possible case of TB, and sputum smears taken. Haemoptysis is an important diagnostic sign; there may be streaking of the sputum with blood or coughing up of fresh blood. A difficulty arises with the HIV-positive person as in this case a chronic cough is not a good indicator of TB; rather, night sweats lasting for more than 3 weeks, combined with a cough or fever of any duration, should be used instead. TB infects people over a spectrum of severity depending on the host response, the dose of organisms and the length of time. The first sign of infection is the primary complex in which the organism is localized to an area of the lung, with a corresponding enlargement of the hilar lymph nodes. In the majority of people, this heals completely or with a residual scar, and the person develops immunity to further challenge. If healing does not occur, then the focus extends to cause glandular enlargement, pleural effusion or cavity formation. The third phase of the disease results from complications of the regional nodes. These may be obstructive, leading to collapse and consolidation, cause erosion and bronchial destruction or spread locally. The final stage is one of bloodstream spread, disseminating bacilli to all parts of the body, where they may produce tuberculous meningitis or miliary infection. Longer-term complications are those of bones, joints, the renal tract, skin and many other rare sites. The risk of developing local and disseminated lesions decreases over a period of 2 years. In the majority of cases, if the disease is going to progress, it will do so within 12 months of infection or 6 months from the development of the primary complex. By the end of 2 years, 90% of complications will have occurred. Bone and other late complications make up a very small proportion beyond this time.

Answer 59

TB is spread by droplet infection, so sputum-positive cases transmit the disease much more efficiently than those whose sputum is negative on microscopy. The risk to the community is therefore from pulmonary TB and the emphasis should be on finding these cases by taking a sputum smear, ideally confirmed by culture. The comparative costs of diagnostic techniques are: Smear 0.02 Culture 0.20 Sensitivity 0.40 Full plate X-ray 1.00 Fifty sputum smears can be made for the equivalent cost of one X-ray, and this comparative cost should be considered when diagnosing cases in the community. Anybody presenting to the health services with a cough for 3 weeks or more should be asked to produce some sputum and a smear made; this is dried and treated with Ziehl–Neelsen stain for acid-fast bacilli. X-ray examination has a high sensitivity so is of more value in countries with a low incidence of TB and plentiful resources, but sputum microbiology is still necessary to confirm the diagnosis and provide cultures for drug-susceptibility testing. A fully automated DNA test, such as Xpert MTB/RIF, which simultaneously detects positive cases and rifampicin drug resistance, is set to revolutionize the diagnosis of TB. It is more sensitive than ordinary sputum smears, which depend upon the accuracy of the microscopist, and gives results within 10 min, so suspected cases can be diagnosed and started on treatment much more rapidly. The test is particularly useful for detecting TB in the person with HIV, as well as the multidrug-resistant case. When a new case is diagnosed, a simpler form of search is made in the house and surrounding households. Any contacts of the case, such as family or friends, are examined to see if anybody has a productive cough or clinical signs, and a smear made. Contacts should be given BCG. Chemoprophylaxis is given to children under 6 years old and to contacts positive for HIV, and followed up at regular intervals. Follow-up information can all be included in the national registration system.

Answer 60

Transmission of tuberculosis is by the airborne route, with coughing and spitting the main methods of disseminating the organism. Many people meet the tubercle bacillus in early life, acquire resistance and are quite unaware of ever having come into contact with it. A proportion, approximately 5%, will manifest the disease in varying levels of severity. This might be nothing more than an enlargement of the primary focus with a few systemic effects, and resolve spontaneously, while other cases may have respiratory symptoms or progress rapidly to bloodstream spread, presenting as a case of miliary infection or tuberculous meningitis. The type and severity of the disease is determined by the host response, but why one person should develop TB and another not cannot generally be determined. There is some evidence that susceptibility may be genetically determined, as people who have suffered from TB, even if adequately cured, are more likely to develop a new infection a second time. Some families are particularly susceptible, as with the famous literary family the Brontës, in which first the mother died from TB, followed by nearly all the children, yet the father never succumbed to the disease. The dose of bacilli might also be important because young children in close contact with an active case more commonly develop severe TB (miliary or meningitis). Factors that are known to reduce resistance are: • young age, especially the first year of life; • pregnancy; • malnutrition; • intercurrent infections such as measles, whooping cough and streptococcal infection; • HIV infection; and • occupations or environments that damage the lung (mining, dust, smoke). As well as variation among individuals, there are also considerable differences in the susceptibility of populations. This can be measured by the annual TB infection rate, which compares the tuberculin reaction of nonvaccinated subjects of the same age every 5 years. With BCG vaccination at birth, this can no longer be done, but data obtained before this became a universal policy are still valid. Another method of estimating incidence is from TB notifications. Environmental factors are also significant in infection, and the population density is as important as its susceptibility. The dose of bacilli that the individual will meet is increased by continued contact over time. This dose/time factor is more likely to be found in conditions of poverty and overcrowding. If the dose is sufficiently large and maintained for long enough, even the defences of the immunologically competent individual may be broken down. The risk of infection is greatest in the young and rises again in the old, so overcrowding increases the opportunity for infection to be acquired at a younger age. As the young mix extensively, they will also have a greater opportunity to pass on the infection. At the other end of life, the elderly often form persistent foci in a community – a potent source of infection to the young. HIV infection has changed the epidemiology and presentation of TB, especially in Africa, leading to more lower lobe and extrapulmonary disease. (There are estimated to be more than 20 million persons worldwide with dual TB and HIV, the majority of these in Africa.) Reduced host response has increased susceptibility and allowed reactivation or reinfection to take place, as well as increasing the likelihood of new infection from a contact or case. However, there is evidence to suggest that HIV/TB patients are less infectious than those with just TB. Conversely, TB patients are more likely to rapidly progress to fullblown acquired immunodeficiency syndrome (AIDS) when infected with the HIV virus. Initially, HIV-infected TB patients commonly present with pulmonary infection similar to the HIV-negative case, but as the disease progresses extrapulmonary TB predominates and other manifestations of HIV disease such as chronic diarrhoea, generalized lymphadenopathy, oral thrush and Kaposi’s sarcoma become more common. All HIV-positive cases should therefore be investigated for TB and all TB cases tested for HIV. Despite the increase in extrapulmonary TB, it is still the sputum-positive case that is responsible for transmission of infection, and this must remain the priority in searching for cases. Consumption of unpasteurized milk may result in bovine TB in humans where the disease is present in the animal population. This presents with enlargement and suppuration of the cervical lymph nodes rather than pulmonary disease. It is now less common than formerly with the testing of cattle and pasteurization of milk, but in developing countries where cattle and their produce are an important part of the diet, such as in Central and South America, bovine TB is still found.

Answer 61

TB may well be one of the most ancient of human diseases, having been detected in bones submerged off the coast of Israel dating to 9000 years ago. It is found worldwide at various levels of severity. In 2013 there were an estimated 9 million new cases, 1.1 million of these being HIV positive; 1.5 million died, of which 360,000 were HIV positive. Fifty-six per cent of cases were in the South-East Asia and Western Pacific regions of the World Health Organization (WHO), with 24% of all cases in India and 11% in China. Twenty-five per cent of all cases were in Africa. Between 1990 and 2013, prevalence rates fell by 41% and continued to decrease slowly each year. Countries of low TB prevalence are defined as those where less than 10% of children under 15 have a positive tuberculin test. These are largely the countries of Western Europe and North America. TB is, however, increasing in Eastern Europe and the former USSR. Nearly the whole of the tropical world has a high prevalence rate, with some countries experiencing over 50% of the under 15 year olds tuberculin positive. Also, urban areas have higher rates than rural areas. There are high rates in Africa and parts of South America. Asia, India, Myanmar, Thailand and Indonesia all have high tuberculin-positive rates too. In the Americas, the indigenous peoples have a much higher TB rate than the nonindigenous. There is a high susceptibility in the Pacific Islands, in which TB was an unknown disease until the arrival of explorers, who introduced the disease.

Answer 62

There are four main strategies for the control and prevention of TB, in the following order of priority: • search and contact tracing for new cases; • adequate treatment of all cases, especially the sputum positive; • improvement of social and living conditions; and • BCG vaccination. Vaccination by BCG induces cell-mediated immunity to the mycobacteria but does not generate humoral immunity, as do other vaccines. BCG vaccination therefore alerts the body’s defences rather than inducing antibody formation. After a BCG vaccination, a primary infection will still take place, but the progressive or disseminated infection will be reduced. BCG protects against miliary and meningitis infection, the worst kinds of childhood TB, but does not have much effect on adult cases, which are generally the source of infection. The effectiveness of BCG varies considerably in different countries. In Europe there is a good response, while in India it is marginal. This is thought to be due to atypical mycobacteria circulating in the environment, so BCG should be given in developing countries at birth or as soon after as possible. In developed countries, BCG is given selectively to high-risk groups, such as immigrants. BCG should not be given to children who are known to be HIV positive, even if they are asymptomatic, nor to pregnant women. BCG is a freeze-dried vaccine given intradermally. Other methods, such as multiple puncture, jet injection or scarification have been found to be not so satisfactory. The vaccine is sensitive to heat and light, so must be carefully protected. Sputum smear examination is a very simple technique for screening populations, especially where there has recently been a case of TB. All contacts of a case should have several sputum smears taken, concentrating on the young and elderly. TB is particularly a disease of poor social conditions and overcrowding, as shown by the remarkable decline of the infection in industrialized countries prior to the advent of chemotherapy. The disease was as bad, if not worse, in Europe at the turn of the century than in many developing countries now, but showed a progressive and continuous reduction of cases as living conditions improved. As standards increased, there was a demand for improved housing with fewer people sharing the same room, so that overcrowding declined. Personal hygiene improved and practices such as spitting disappeared almost completely.

Answer 63

The functions of chemotherapy can be summarized as follows: • Treat individual cases to reduce morbidity and mortality. • Reduce the number and period of infectious cases. • Provide a method of disease reduction in developing countries where the raising of social standards would take some time to achieve. • Prevent the emergence of resistant strains. A newly diagnosed case of TB should be treated with a four-drug regime for 2 months, consisting of: Isoniazid 300 mg daily Rifampicin 10 mg/kg up to 600 mg daily Pyrazinamide 35 mg/kg up to 2 g daily Ethambutol 25 mg/kg daily After the 2-month period, isoniazid and rifampicin only are taken daily for a further 4 months. In areas of known isoniazid resistance, then a three-drug regime of isoniazid, rifampicin and ethambutol is taken for the 4-month period. In cases of miliary or meningitis TB or bone/joint disease, treatment should continue for 9–12 months. In a case where retreatment is required or drug resistance is suspected, then streptomycin at 15 mg/kg daily is added to the four-drug regime for 2 months, then the four-drug regime is continued for a further month, and isoniazid, rifampicin and ethambutol for 5 months. Once the drug susceptibility test (DST) result is known, the regime can be modified accordingly. Early and adequate treatment is essential if drug resistance is not to develop. Sadly, there are now many cases of multidrug-resistant TB (MDR-TB), resistant to both isoniazid and rifampicin. A link with HIV infection has shown the development of MDR-TB to occur twice as often in patients with both TB and HIV. These cases will need to be put on MDR regimes, which include more drugs, are expensive and need to be taken for a longer period. Very welcome progress has been made in the treatment of TB by the introduction of several new drugs: bedaquiline, delamanid, linezolid, rifapentine and terizidone. WHO has drawn up guidelines for their introduction and monitoring to decide on the best combinations. Delamid has been used in combination to treat MDR-TB cases. A more serious problem has been the development of extensively drugresistant TB (XDR-TB), a virtually untreatable form of TB. This is particularly prevalent in Eastern Europe, Russia and Central Asia. Considerable expenditure and strict control will be required to contain this problem. Prophylaxis with daily isoniazid (300 mg) for 6 months can be given to close contacts under 35 years of age and people with HIV, and to babies (5 mg/kg) born to mothers who develop TB shortly before or after delivery. The WHO’s Stop-TB strategy (also known by the ‘brand name’ DOTS – Directly Observed Therapy, Short-course) includes political and financial commitment, standardized diagnosis, treatment and adherence support, and monitoring. Until recently, this strategy recommended that all cases should have directly observed therapy (DOT) to ensure adherence. However, evidence from randomized trials has shown that DOT (as opposed to self-administration) does not improve cure rates. For all patients, WHO recommends good education on the diagnosis of TB and importance of treatment adherence. Patients should choose a treatment supporter, who is someone who is accessible, concerned and reliable, such as a family member or community health worker/volunteer. The treatment supporter encourages the patient when they are feeling demotivated, and to keep follow-up appointments and take the right tablets for the full course of treatment, until cured.

Answer 64

A system to follow up all diagnosed cases of TB discharged from a hospital or health centre is required on the following lines: • Register the case with a central registry on diagnosis. • When the patient is discharged, inform the registry, the nearest clinic to the person’s home and the supervising doctor. • The clinic ensures the patient receives regular follow-up treatment or goes and finds them if they default. • The supervising doctor visits on a regular basis to check the clinic records and make sure that the registered patients are receiving treatment. • When the full course of treatment is completed and the doctor is satisfied that the patient is cured, the central registry is notified. Reminders and double checks can be built into the system, such as the central registry sending out quarterly checks on each patient. The sophistication of the system depends on the resources of the country, but lack of resources is never an excuse not to have a system at all. To not follow up a partially treated patient is a waste of expensive hospital treatment, encourages the development of resistant organisms and increases the risk to the community. Follow-up is always cheaper than re-diagnosis and treatment. Evaluation of TB control programmes is by measuring the proportion of new smear-positive cases that are cured or are certified to have completed treatment. The WHO target is 85%. Other useful indicators are: • annual rate of new TB cases diagnosed; • rate of sputum-positive cases diagnosed; • proportion of children under 5 years of age diagnosed; • proportion of miliary and meningeal TB; • rate of sputum smears examined; • rate of BCG scars, on survey; • relapse rate; and • rate lost to follow up. A decrease in the proportion of children under 5 years of age diagnosed and of those with miliary and meningeal TB will indicate improvement; however, this will need to be confirmed by a sputum smear survey. Nursing staff should be taught to always give the BCG vaccination in the same place, normally the deltoid area of the left arm, so that touring staff, schoolteachers, etc. can rapidly examine a group of children. Not only is the standard treatment regime for TB likely to use newly introduced drugs, but new diagnostic techniques are also likely to be introduced over the next few years. In order to facilitate these changes, WHO has established a Stop TB Partnership to prepare countries for the introduction of these new tools in order to minimize the delay between licensure, availability and adoption.

Answer 65

A number of different organisms produce infection, including Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, influenza, rhinoviruses, adenoviruses, metapneumovirus and respiratory syncytial virus (RSV). The most important of these are S. pneumoniae or the pneumococcus, H. influenzae bacteria, and RSV and parainfluenza viruses. As well as there being a wide range of viruses, each species may have a number of serotypes, with new ones appearing from time to time. Hosts defend themselves by producing an appropriate immune response, but because of the large number of serotypes this is a continuous process. Infection will cause illness in some people but not in others who have developed an immune response either to the specific organism or to an antigenically similar serotype. New antigenic mutations, as occur in influenza, can cause epidemic or pandemic spread because no prior contact with the new variant has been made.

Answer 66

ARIs are divided into upper respiratory and lower respiratory, the former producing a runny nose, sneezing and headache, while the main symptoms of lower respiratory infection are a cough, shortness of breath and inward drawing of the bony structure of the lower chest wall during inspiration, which is called chest indrawing. Both are generally accompanied by fever. The main pathological feature is pneumonia, which can either be lobar or bronchial. In lobar pneumonia, one or more well-defined lobes of the lung are involved, whereas in bronchial pneumonia the condition is widespread.

Answer 67

Identifying the organism by culture of the sputum can be attempted where facilities permit, but in most developing countries ARI will be diagnosed on clinical criteria.

Answer 68

Acute respiratory infections are transmitted by coughing out a large number of organisms in an aerosol of droplets, which are either breathed in, enter via the conjunctiva, or land on surfaces and subsequently enter mucous membranes from fingers. (See further under influenza, Section 13.3.) Susceptibility and response is determined by host factors, some of which are: • Age. Young children develop obstructive diseases such as croup (laryngotracheobronchitis) and bronchiolitis. Tonsillitis is commonest at school age, whereas influenza and pneumonia are important causes of death in the elderly. In young children, mortality is inversely related to age. • Portal of entry. Volunteers have been more easily infected by some organisms applied to the conjunctiva than through the nasopharynx. • Nutrition. Low birth weight and malnourished children have a higher morbidity and mortality. Certain nutritional deficiencies, such as lack of Vitamin A and zinc, contribute to the development of a more severe disease and higher death rate. Breastfeeding appears to have a protective effect. • Socio-economic. ARI is a disease of poverty with higher incidence in lower socio-economic groups and those that live in urban slums. Higher rates of lower respiratory disease have been found with increasing family size. Much of the reason for this increase appears to be due to increased contact and agglomeration, as shown in children attending day-care facilities or school, where infection occurs irrespective of social class. • Air pollution. A correlation with domestic air pollution has been shown in South Africa and Nepal. Passive smoking may affect pulmonary function and make the child more susceptible to infection as well as influence the child to become a smoker. • Climate. More respiratory infections are found in the cooler parts of the world or in the higher altitude regions of the tropics. There is a distinct seasonal effect in many countries, with more respiratory infections in the winter. However, cold alone is not a causative factor. The ‘cold’ derives its name from the belief that becoming chilled or standing in a draught is responsible, but when volunteers are subjected to these stresses and inoculated with rhinoviruses, they develop no more ‘colds’ than controls. In the tropics, respiratory infections occur more commonly with the rains. • Other infections. Any infection that causes damage to the respiratory mucosa will allow a mild infecting organism to progress to more serious consequences. The most important of these diseases is measles, post-measles pneumonia being particularly common.

Answer 69

Worldwide, the most important cause of death in | children in developing countries.

Answer 70

The first line of action is to assess the severity of illness and give treatment. This is supportive therapy for mild infections and the active administration of antibiotics to the severe case. The mild infection is best treated at home and kept away from sources of other infection, which may cause more serious disease, while the severe case requires early treatment to prevent complications and death. In children, the respiratory rate and chest indrawing are used to decide management: • Mild cases with a respiratory rate of less than 40 breaths/min in children 2–12 months old, and 50 breaths/min in children 1–5 years old, are treated at home with supportive therapy. The mother should be encouraged to nurse her child, giving him or her plenty of fluids (breastfeeding or from a cup), regular feeding, cleaning the nose, maintaining the child at a comfortable temperature and avoiding contact with others. • Moderate cases with a respiratory rate over 40 breaths/min in under 1 year olds and 50 breaths/min in children 1–5 years old, but with no chest indrawing, should be given antibiotics (oral co-trimoxazole (4 mg/kg twice daily); oral amoxycillin (15 mg/kg three times a day); or intramuscular penicillin G) and nursed at home. • Severe cases with chest indrawing, cyanosis or cases too sick to feed must be admitted as inpatients and given active support as well as treatment with antibiotics.

Answer 71

The first step in management of a child with ARI is to separate the mild from the moderate and to treat the moderate and severe. The essence is speed and active treatment. This can easily be taught at primary health-care level. The mother can be educated on the management of her child with a mild infection and when to refer it. It is the delay in referral and treatment that will allow a moderate case to become severe and the severe case to die. The village health worker can identify and treat the mild or moderate case of ARI using simple diagnostic criteria and a standard treatment protocol. Measuring the respiratory rate and knowing which action to take are the most important aspects. Training and supervision of primary health-care workers is a priority in the management of ARI. Preventive actions that can be undertaken are: • Reduce contact. Acute respiratory infections are just as common in industrialized countries as they are in developing countries, but infant deaths from respiratory infections in the former have declined. The reason would appear to be due to smaller families and greater birth intervals, permitting increased individual care of children and better nutrition. The child is reared at home and does not need to be carried around where he or she is exposed at a very young age to infecting organisms. • Good nutrition. Well-nourished children are in a stronger position to defend themselves against any infection. Encourage breastfeeding, especially during early stages of illness. Providing additional nutritional support to children with measles can prevent them developing post-measles pneumonia. • Health education. Teach people to cough away from others, cover the mouth when coughing, not to spit or smoke and provide proper ventilation for smoke and fumes. • Vaccination of childhood infections. The danger of developing pneumonia after measles is a serious problem, so prevention of measles will reduce the severe forms of ARI. Indeed, measles vaccination is perhaps the single most effective preventive method. The routine childhood vaccination programme offers protection from pertussis, diphtheria, H. influenzae and the pneumococcus, as well as TB. • Other vaccines. Influenza vaccine is prepared annually according to the expected strain of influenza and should be given to those at risk (e.g. immunocompromised and those with chronic respiratory infections) if facilities allow. Vaccines against RSV, parainfluenza and the adenoviruses are in preparation.

Answer 72

Measles generally occurs in seasonal epidemics, which can be forecasted and top-up vaccination given. Influenza occurs annually or in pandemics with warning given of strain of organism and vaccine composition, allowing sufficient time for persons at risk to be protected.

Answer 73

m. There are three types of influenza virus, A, B and C. The surface of the virus is coated with haemagglutinin (H antigen with 16 subtypes) and an enzyme, neuramidase (N antigen with nine subtypes). The virus is designated as A(H1N1), A(H2N2) . . . A(H3N2), etc. with, in addition, the site of isolation, culture number and year, e.g. A/Beijing/262/95(H1N1). Influenza A is the least stable, with antigenic shift of the H and N antigens, influenza B is more stable and influenza C is the most stable with low pathogenicity (producing mainly subclinical infection). Antigenic drift in both A and B viruses produces new strains and is responsible for the frequent epidemics that occur at regular intervals

Answer 74

Influenza presents with fever, malaise, muscle aches and upper respiratory symptoms of sudden onset. Headache, anorexia and sore throat are common features. The uncomplicated illness lasts about 5 days. There is initially a dry cough, but this can be severe or secondary infection can ensue, predominantly with Streptococcus pneumoniae, Staphylococcus aureus or Haemophilus influenzae, and this is the main cause of mortality. Other than pneumonia or acute bronchitis, infection can lead to otitis media in children and cardiac damage in adults. Reye’s syndrome in children and encephalitis in adults are serious, although uncommon, complications. Influenza is a serious infection in the elderly, with high death rates. When a major antigenic shift occurs as it did in 1957 (the Asian flu pandemic), then all ages are susceptible and the number of deaths can be considerable. In developing countries, influenza can be a more serious infection; the 2002 epidemic in Madagascar had a 3% case fatality rate, the majority of deaths being in young children. Also, a common sequela of influenza is pneumonia, a major cause of death in children in developing countries. Influenza B tends to be a childhood infection, so that once immunity has been built up protection has been acquired to the more stable virus. Infection in childhood also produces some cross immunity, but reinfection with both A and B does occur. Subclinical infection occurs frequently, boosting the pre-existing immunological memory. Previous exposure to strains within the same subtype will, to a certain extent, lessen the clinical impact of closely related strains, reducing the viral load and infectiousness. On a community-wide basis, this cross-reactive herd immunity will lessen the severity of the epidemic

Answer 75

Diagnosis is on clinical grounds, taking care to differentiate influenza (occurring seasonally or in epidemics) from other causes of respiratory infections, especially the common cold. Direct immunofluorescence (DIF), enzyme-linked immunosorbent assay (ELISA) or RNA amplification can be used to make the diagnosis, with polymerase chain reaction (PCR) now the method of choice in influenza-detection laboratories. Virus can be isolated from pharyngeal or nasal secretions and cultured in specialist centres.

Answer 76

Transmission is by respiratory droplets through sneezing or coughing, but can also be by direct contact with mucus- or droplet-contaminated surfaces. The amount of virus shed is correlated with the severity of symptoms and fever, peaking in the early course of the disease, although pre-symptomatic and asymptomatic transmission can also occur. Children and immunocompromised individuals shed virus for longer periods and in higher titres. Droplets are comparatively large (>5 mm) and can be projected up to 3 m, but are more likely not projected further than 1 m. They infect people directly when they settle on the mucous membrane of the nose or mouth (and possibly the conjunctiva) or indirectly when they land on surfaces. Airborne transmission can also occur from smaller particles derived from dried-out droplets that become aerosolized. These result in aerosols of particles in dust from contaminated surfaces but are more likely from medical procedures such as manual ventilation, suction and bronchoscopy. Aerosol transmission might also occur in systems where air is recycled, such as in aircraft. However, longdistance transmission does not occur. Contact transmission is probably more important than previously thought, with virus remaining for long periods of time on hard non-porous surfaces. This is then transferred by hand to the individual or from person to person, infection taking place through mucous membranes. Influenza is highly infectious and spreads throughout whole communities, potentiated by overcrowding and frequent social contact, such as at the workplace or in markets. The natural reservoir of influenza is in birds, particularly aquatic species (ducks and geese), while the pig is important because it is susceptible to infection both from birds and humans, so new mixed infections can develop. The close association of humans with domestic birds and animals, particularly in south China, is thought to be where most new variants have arisen (see further in Section 19.2).

Answer 77

Period of communicability is 2 days before onset of symptoms to 5 days after.

Answer 78

Occurrence and distribution. Influenza A is responsible for pandemics and regular seasonal outbreaks and influenza B for smaller localized outbreaks, while influenza C produces mild infections. In the tropics, epidemics tend to occur in the rainy season, while in temperate climates influenza is nearly always a disease of the winter months. Pandemics have occurred in 1889, 1918, 1957, 1968, 1977 and 2010 (swine flu). Several epidemics of avian flu A(H5N1) since 1997, and especially in 2006 and 2007, caused considerable concern because of the number of human cases (382), and the high fatality (241 deaths) that also occurred. Fortunately, there was no evidence of a major antigenic shift in A(H5N1) to suggest that humans would now be susceptible, with only some limited occurrences of human-to-human transmission. (See further in Sections 19.1 and 19.2.) Another form of avian influenza, A(H9N2), has been responsible for several mild human cases. In 2010, A(H1N1) swine flu, which had originated in Mexico in 2009, reached pandemic proportions with cases in all parts of the world, but fortunately was not as severe as had been anticipated. It predominantly affected younger age groups, and pregnant women had a four times greater risk of developing severe disease than the general population. (See further in Sections 18.2 and 19.2.) The pandemic continued into 2011 in the northern hemisphere, but with a death rate little different from that expected from seasonal flu. Seasonal influenza epidemics in the years immediately following a pandemic tend to be relatively severe.

Answer 79

Control and prevention. As influenza is so infectious, the majority of the population becomes infected during an epidemic, but any reduction of social contact, particularly in crowded places, can reduce this likelihood. Spitting should be outlawed and people encouraged not to cough directly at other people. Infected persons should stay at home and not go to a health centre or hospital. People should be advised to cough into tissues, which are disposed of immediately. Antiviral-impregnated tissues have been found to be valuable in the reduction of some upper respiratory infections. Hand washing and regular cleaning of surfaces with ordinary cleaning products are now considered to be major methods of reducing transmission. Fluid-repellent surgical masks will offer some protection when in close contact with an infectious case, as long as the mask is not handled and droplets then transferred to mucous membranes. Infected persons should be encouraged to wear masks when in contact with people. Influenza vaccine is available for protecting at-risk persons, such as people over 65, those with chronic chest or kidney disease and the immunocompromised. The difficulty of producing a vaccine is that a new one has to be made each year containing the expected composition of antigenic subunits. The WHO collaboration centres, with reference laboratories throughout the world, provide advance warning to assist countries producing vaccine, but new techniques such as virus manipulation to anticipate natural change in the virus could allow banks of virus to be kept in store. At present, WHO recommends the inclusion of an A(H1N1) and A(H3N2) subtype and a single B virus, but each year different strains will be required. The use of vaccines in a pandemic situation to protect the population in an unaffected country or area is a distinct possibility, concentrating on school-aged children, as they have the highest transmission rates. This would be particularly important in highly lethal forms of the virus such as A(H5N1), where people coming into close contact with poultry would be the target population. The development of new vaccines may provide protection for longer periods and allow the possibility of vaccinating populations against influenza outbreaks. Due to the high transmission potential of children, from 2015 all schoolchildren in years one and two in England and Wales will be given flu vaccine. Potentially children in the age range 2–17 years could benefit and reduce the amount of transmission to the rest of the population, so coverage may be increased in the future. Pneumococcal vaccination programmes (see Section 13.8) will do much to reduce secondary infection and serious disease to develop

Answer 80

Treatment. There is no treatment, but antiviral agents will reduce the duration of fever and severity of symptoms and can be stockpiled when there is risk of an epidemic. Neuramidase inhibitors such as oseltamivir (Tamiflu®) and zanamivir, or the less useful M-2 channel blockers such as amantidine and rimantidine, can be used. They can also be given prophylactically, but widespread use has resulted in the development of resistance. Antivirals are particularly valuable in reducing the development of secondary infection in vulnerable people, but antibiotics might also be required. In individual cases, antibiotic sensitivity should first be determined, but in epidemic situations stockpiles might need to be kept of doxycycline, co-amoxiclav (amoxicillin plus clavulanate) or ciprofloxacin.

Answer 81

Surveillance. Sentinel reporting centres with an agreed case definition probably provide a better idea of the influenza situation than collecting data of variable quality from every clinic and hospital. This can be compared with laboratoryconfirmed cases where facilities permit. WHO reports on the global situation in the Weekly Epidemiological Record (WER) from a worldwide network of reporting centres. More detailed information can be obtained from the Flu Net website, which provides up-to-date information from the Global Influenza Surveillance Network (GISN) and other national reference laboratories. Data are provided on virus subtypes and their global movement in the form of maps and graphs.

Answer 82

Organism. Bordetella pertussis. Bordetella parapertussis produces a milder disease.

Answer 83

Clinical features. Illness commences with upper respiratory symptoms, fever and a cough, which becomes paroxysmal with the characteristic whoop, or sometimes ends in vomiting. The classic ‘whooping’ disease is not seen in children under 3 months of age, when instead they have attacks of cyanosis and stop breathing. Whooping cough is a serious disease if it occurs at a young age, the severity being inversely proportional to age. A mild infection in the older child, it becomes an important cause of death in the very young

Answer 84

Diagnosis is mainly on clinical criteria, but culture of the organism from a nose or throat swab can be attempted, although the organism is difficult to grow. PCR can be used to confirm the diagnosis.

Answer 85

Transmission is via airborne spread of droplets, particularly during the early stage of illness. Older children and adults may have such a mild infection that their importance as a source of infection is not realized. Vaccinated individuals can have subclinical infection in which organisms are disseminated.

Answer 86

Period of communicability is 4 weeks from the first symptoms, being most infectious in the first week, before the paroxysms start.

Answer 87

Occurrence and distribution. Whooping cough is a serious disease in tropical countries, contributing to high rates of infant mortality. Vaccination programmes have markedly reduced the disease in the temperate regions of the world, but where the vaccination programme has decreased or been abandoned, it has rapidly returned as a major health problem. Where the young infant is always carried around by its mother, there is an increased opportunity for exposure, coming into close contact with other children who might be infectious.

Answer 88

Control and prevention. Isolation of cases, especially of young children and infants, should be instituted. Infective children should be kept from school, markets and any place where young children are likely to congregate. Known contacts of a case of whooping cough (e.g. in the extended family of a case) should be given a booster vaccination if they have been vaccinated before, otherwise they should receive prophylactic erythromycin and vaccine. The median age for the disease is 2 years, but because of its severity, vaccination should be started at 1–2 months. Three doses of vaccine are given, normally combined with tetanus and diphtheria as triple vaccine. Antibodies to pertussis decrease rapidly, even after a three-dose course, and WHO now recommends a booster dose between 1 and 6 years, ideally around 2 years. There are two types of vaccines: whole-cell (wP), used in most programmes, and acellular (aP), favoured by developed countries. aP contains no cellular component, so can be given to children over 6 years of age and to the pregnant woman in the third trimester of pregnancy to give protection to the very young infant.

Answer 89

Treatment. Erythromycin or azithromycin is only effective when given in the first week of the disease. Fluid loss is an important cause of mortality, so mothers should be encouraged to give extra fluids and breastfeed immediately after a coughing bout.

Answer 90

Surveillance. In many countries whooping cough is a notifiable disease.

Answer 91

Organism. Corynebacterium diphtheriae and, rarely, Corynebacterium ulcerans.

Answer 92

Clinical features. Diphtheria produces both local and systemic effects. The organism can infect the tonsils, pharynx, larynx, nose or skin, forming a pale grey membrane and local inflammation. Symptoms are fever, sore throat and enlarged cervical lymph nodes in the pharyngeal form, bloodstained discharge in the nasal form and skin ulcers in the cutaneous form. The inflammatory reaction produced in the respiratory tract can lead to swelling of the neck and respiratory obstruction. From the primary site, exotoxin is produced, which can cause myocarditis or neuropathy, especially cranial nerve palsies.

Answer 93

Diagnosis. Throat, nose or skin swab of the exudate. A culture of the organism should be sent to a reference laboratory if possible.

Answer 94

Transmission. Diphtheria can be transmitted by: • airborne transmission of droplets; • direct contact with lesions and exudates; • indirect contact through articles soiled with discharges; and • ingestion of contaminated milk. In a non-immunized population there is a high incidence of carriers and a low incidence of cases in a ratio of approximately 19:1. Between 6% and 40% of children are infected each year, so that by 5 years old some 75% have been infected and by 15 years old nearly all. This means that by 15 years of age the majority of children have developed immunity, either through a subclinical infection or one in which clinical symptoms were revealed

Answer 95

Occurrence and distribution. Commonly a disease of children, diphtheria can occur in non-immunized adults with serious results. Outbreaks of the disease are seen, but it is probably a much more frequent disease than realized, as subclinical transmission through skin, and possibly nasal lesions, maintains immunity. This was probably the situation in many tropical countries, but now universal childhood vaccination programmes are protecting young children. A breakdown of these programmes, or remaining pockets of unvaccinated adults, leads to serious disease.

Answer 96

Control and prevention. Diphtheria is prevented by vaccination of all children with three doses of diphtheria toxoid. This is normally combined with pertussis and tetanus as a triple vaccine (DTP), commencing in the first or second month of life. A booster dose should be given between 1 and 6 years of age. As with polio and rubella vaccination, diphtheria immunization shifts the likelihood of disease to an older and more dangerous age, so complete coverage of all children is imperative. Adults visiting an endemic country from one in which the vaccination status is good should have an adult type booster Td (tetanus and diphtheria) in which the concentration of toxoid is reduced. Ideally, adults, particularly travellers, should have booster doses of Td every 10 years. This applies equally to adults living in countries with a poor vaccination coverage. In the event of an outbreak, previously vaccinated contacts should be given a dose of Td and those not vaccinated should be given Td and an antibiotic (erythromycin or penicillin).

Answer 97

Treatment. If diphtheria antitoxin is available, it should be given to cases following a test dose for hypersensitivity. Erythromycin or procaine penicillin G should be used for specific treatment

Answer 98

Surveillance. Diphtheria is a notifiable disease in most countries.

Answer 99

Organism. Neisseria meningitidis. Twelve serogroups have been identified, but of these A, B, C and Y are the most important in producing disease, while A and C and W135 predominate in epidemics

Answer 100

Clinical features. There is a sudden onset of fever with severe headache, vomiting, neck stiffness and progressive loss of consciousness. A petechial rash, which does not blanch, is an important sign in pale skins, but is not seen on black skins. Infants show floppiness and high-pitched crying, while children may present with convulsions. Normally the diagnosis is easy to make from the rigidity of the neck stiffness and the history, but in the infant it can be more difficult. The other main cause of high fever, headache and vomiting in tropical countries is cerebral malaria, from which the disease must be differentiated.

Answer 101

Diagnosis is by lumbar puncture, but should not delay early treatment, which can be given straight away. A Gram stain is only reliable in some 50% of cases, so culture should be attempted wherever possible and data on antibiotic sensitivity obtained. Blood should also be taken for culture and PCR. Smears from petechiae can also be examined by Gram stain. Group-specific meningococcal polysaccharides can be identified in the cerebrospinal fluid (CSF) using latex agglutination and, where there are the facilities, specific DNA can be detected.

Answer 102

Transmission is by airborne spread of droplets and from direct contact with secretions from the nose or throat. The organism is found commensally living in the nasopharynx, so other factors must also be responsible for meningitis to occur. Epidemic meningitis was first studied in cooler climates and an association found with overcrowding, especially in military institutions. The organism, when introduced into an overcrowded environment, produced both cases and carriers (nasal). As the number of carriers increased, the number of cases of meningitis did so likewise. In the African (Sahel) region, epidemics occur in the cool dry season when cold nights encourage people to sleep indoors, often in overcrowded situations (Fig. 13.4). This is also the time of the year when the dry, dust-laden wind, the Harmattan, blows, which dries out the respiratory mucosa, and is the time of the year when upper respiratory infections are more common too. Movements of people take place as a result of pilgrimages, and traditional markets potentiate the transfer of infection. The organism inhabits the nasal mucosa within which it is anatomically very close to the meninges, although these are separated by formidable barriers of bone and membrane. The generally accepted theory is that the organism passes from this site into the bloodstream, crosses the blood–brain barrier and enters the CSF. Difficult though the direct route may seem, it has been shown that minute passages through the bone of the skull do occur and transmission of organisms along this route is a possibility as well. Furthermore, if organisms are introduced directly into the subarachnoid space, infection will only occur if a critical level is exceeded (10 3 organisms in dogs), suggesting that this route could frequently be invaded, but only when there is excessive infection does meningitis develop.

Answer 103

Occurrence and distribution. Meningococcal meningitis occurs in epidemics, especially in the Sahel part of Africa in a band stretching from Senegal to Ethiopia (Fig. 13.4). The epidemics are markedly seasonal, occurring in the early, coolest part of the year when the relative humidity is at its lowest. With the arrival of the rains, the epidemic abates (Fig. 13.5). The amount of rainfall (1100 mm) delineates the southern boundary of the meningitis belt, and the northern boundary is the desert. Within this area, major epidemics, mainly of group A, occur at 7- to 14-year intervals, with lesser ones in between. As well as the meningitis epidemic belt in Africa, there have also been epidemics of group A organisms in India and Nepal, and of group B in the Americas, Europe and Pacific Island nations. More recently, W135 epidemics have been associated with the annual hajj, either with the main gathering in Saudi Arabia or from pilgrims returning to their home countries. Epidemic meningitis is commonest in the age group 5–15 years, with males more frequently affected than females. Only about 1 in 500 persons infected with the organism will develop meningitis. Large, poor families, and other conditions where there is overcrowding, such as at religious and social gatherings, and in refugee camps and labour lines, make meningitis more likely.

Answer 104

Control and prevention. Overcrowding encourages the transfer of the infecting organism and the carrier state, as well as increasing the dose of bacteria that may be transmitted, so all efforts should be made to reduce overcrowding. It may be necessary to close schools and reduce collections of people, such as at markets and religious gatherings, if an epidemic has started or appears likely to do so. In the long term, improvement of housing and family planning will have an effect. Chemoprophylaxis with ciprofloxacin should be given to close contacts, such as all family members, school friends and anyone sharing a large communal sleeping place (such as a dormitory). Rifampicin 10 mg/kg twice daily for 2 days or, if still sensitive to sulfonamides, sulfadiazine 150 mg/kg for 2 days can be used. Chemoprophylaxis is not recommended in large epidemics. There are several vaccines containing either A and C, or A, C, Y and W135 or B. Unfortunately, the very young and those with acute malaria develop reduced immunity. There is also a genetic variation, with some ethnic groups having a poor response. Due to these different factors, duration of immunity is variable, from 3 years or less in young children, and must be measured for each community when formulating a vaccination programme. Vaccine can be used to immunize those most at risk, concentrating on the 2–20-year age group, and household contacts of cases. When there is an epidemic, mass vaccination should be given to communities in the affected area, including vaccinating children below 2 years of age. Epidemic awareness has been lowered to three suspected cases/100,000 in 1 week in a population of over 30,000 and two suspected cases/100,000 in 1 week in a population of less than 30,000, indicating the need to start mass vaccination. Everyone attending the hajj must be vaccinated with ACYW135 vaccine. A conjugated C vaccine has been found to be effective in all age groups, especially young children, and in several countries this vaccine is included in the national childhood vaccination programme (see Section 3.2.2). If an epidemic is found to be due to a group C organism, then this vaccine should be used. A combined A and C polysaccharide vaccine can be given as a single injection to children over 2 years of age to provide several years of protection. A conjugate vaccine for meningitis A (MenAfriVacc) recently developed in India is more effective than the polysaccharide vaccine. A campaign is now in operation to target 15 countries in the meningitis belt. As of January 2015, 217 million persons had been vaccinated. WHO recommends that countries completing mass vaccination campaigns should introduce meningococcal A conjugate vaccine into their routine childhood vaccination programmes within 1–5 years following campaign completion, along with a one-time catch-up campaign for birth cohorts born since the initial mass vaccination. Meningitis B vaccine has now been given clearance for general use and was introduced into the routine childhood vaccination programme in the UK from 2015, with the likelihood that other countries will soon follow. WHO has established an International Coordinating Group (ICG) on Vaccine Provision for Epidemic Meningitis Control to provide access to vaccines and treatment. It also encourages a two-pronged strategy of epidemic preparedness (improved surveillance and case finding) and epidemic response (stockpiling of vaccines and epidemic management strategy).

Answer 105

Treatment may need to be organized on a massive scale when an epidemic occurs by using dispensers, schoolteachers or other educated people to care for isolated communities. Temporary treatment centres (schools, churches, warehouses, etc.) may need to be set up, rather than bringing people into hospital. Benzyl penicillin, ampicillin or chloramphenicol should be used, but in many countries resistance to these antibiotics will require the use of ceftriaxone or one of the cephalosporins. If the organism is unknown, chloramphenicol is used. In epidemics, long-acting chloramphenicol in oil preparations, given as a single injection, avoids the problem of repeat injections. Dehydration is common and intravenous fluids may be required initially, followed by frequent drinks administered by an attending adult.

Answer 106

Surveillance. The regular epidemics that occur in Africa can be forecast and a state of preparedness put into action. Increased surveillance should be undertaken at this time using case detection and increased searches by laboratories. When a case of meningitis is detected, all contacts should be examined with nasopharyngeal swabs. Subtyping of the organism can assist in mapping out epidemics.

Answer 107

Clinical features. H. influenzae can cause a range of illnesses, the most important being meningitis and pneumonia. In meningitis, there is fever, vomiting, neck stiffness and a rigid back in older children; in infants there is a bulging fontanelle. H. influenzae is a common cause of secondary infection in measles and other respiratory infections, resulting in pneumonia (see Section 13.2). Other infections are conjunctivitis in the newborn, otitis media, epiglottitis, cellulitis, septic arthritis, osteomyelitis, empyema and pericarditis.

Answer 108

Diagnosis. The CSF is often purulent, but this can occur in other causes of meningitis (see Table 13.2.), so cultures of the CSF or blood should be made. Latex particle agglutination is a sensitive method of diagnosis, but PCR is preferable where it is available.

Answer 109

Transmission. Airborne transmission of droplets and direct contact with nasopharyngeal secretions. The organism is carried asymptomatically in the nose of carriers, who are often the source of infection to infants.

Answer 110

Period of communicability. Chronic nasal infection can remain for a prolonged period.

Answer 111

Occurrence and distribution. H. influenzae used to be the commonest cause of meningitis in infants and young children under 5 years old, mainly 4–18 months of age. At present it is still a serious problem in some developing countries, but with the advent of universal Hib vaccination the incidence is likely to decline considerably, as it has done in developed countries.

Answer 112

Control and prevention. Routine vaccination of all children with Hib vaccine is now recommended. Vaccine should be given at the same time as DTP vaccine or as a combination vaccine (DTP/Hib). Countries might decide to give a booster dose at 12–15 months, but in most developing countries H. influenzae infection occurs before this age. Where vaccination programmes are starting or catch-up vaccination of adults and children over 18 months is to be given, then a single dose of vaccine is sufficient. Hib can safely be given at the same time as meningococcal vaccine. In the event of an outbreak of several cases of meningitis, vaccination should be given to all children aged under 5 years within the area. Contacts of all ages in households or close communities where there are unvaccinated children should be given prophylaxis with rifampicin. (See also Section 13.6.)

Answer 113

Treatment is with ampicillin, cephalosporin or a fluoroquinolone.

Answer 114

Surveillance. All family and contacts of a case of meningitis should be investigated by nose swabs. Children under 5 years of age that have been in contact with a case should be followed up and treatment started if they develop early signs, such as fever.

Answer 115

Organism. Streptococcus pneumoniae, the pneumococcus.

Answer 116

Clinical features. S. pneumoniae is the commonest cause of ARIs and pneumonia, presenting with a cough, fever and rusty coloured sputum (from bloodstaining). Both bronchopneumonia and lobar pneumonia result, leading to a high mortality in infants and the elderly. S. pneumoniae is also the commonest cause of otitis media, causing fever and pain in the ear. If untreated, this can lead to bacteraemia and fulminant meningitis, with a high fatality rate. There is a high fever and lethargy, and the patient rapidly descends into a coma. S. pneumoniae is also a common cause of conjunctivitis

Answer 117

Diagnosis is by culture of sputum, blood, eye discharges or CSF. A Gram stain will show the characteristic blue-staining diplococci, providing a rapid diagnosis, but culture should also be done

Answer 118

Transmission is normally airborne by spread of droplets during sneezing or coughing from infected persons or healthy carriers. Some 25% of people carry S. pneumoniae in the nasopharynx, although these might not all be disease-producing serotypes. Transmission can also be by direct contact or through articles soiled with secretions, such as handkerchiefs or cloths used to wipe the eye in conjunctivitis.

Answer 119

Period of communicability is as long as secretions are produced in the clinical case, but the importance of healthy carriers is unclear, with some possibly responsible for producing infection in the young or elderly over a considerable length of time. Adequate treatment should render the case or carrier noninfectious within 2 days.

Answer 120

Occurrence and distribution. Worldwide distribution, especially in developing countries, with ARI a major cause of mortality in children. It is one of the commonest causes of terminal pneumonia in the elderly in the developed world. Overcrowding and deprived socio-economic conditions favour disease. Miners and people living in smoke-filled huts, such as in Papua New Guinea, have an increased incidence.

Answer 121

Control and prevention. Active management and treatment of cases of ARI and pneumonia should be implemented as covered in Section 13.2 above, and for otitis media in Section 13.9 below. Family planning and the reduction of overcrowding will reduce the situation in which the infection commonly spreads. Smoking should be discouraged and houses designed so that smoke is taken away from inside the house. Hand washing and the careful disposal of discharges from the nose, throat and the infected eye should be practised. The pneumococcal conjugate vaccine (PCV) has been shown to be highly efficacious against invasive pneumococcal disease but only moderately efficacious against otitis media. The vaccine is now included in the routine childhood vaccination programmes in many countries, including, where funds permit, in developing countries. Priority should be given to countries with a high prevalence of HIV, and in other conditions that increase the risk of pneumococcal disease, such as sickle-cell disease. PCV is most conveniently given at the same time as DTP vaccination, but when first introduced a single catch-up dose may be given to unvaccinated children at 12–24 months and to high-risk children at 2–5 years of age. The childhood vaccination programme has produced considerable herd immunity, protecting unvaccinated children and people over 65 years of age. However, several of the serotypes used in the vaccine have been replaced by other serotypes. So far this has not been a problem except with otitis media, which in one study showed an increase. Pneumococcal polysaccharide vaccine (PPV) can be given to those over 65 years of age and other adults at risk.

Answer 122

Treatment. Penicillin G or erythromycin are effective in the majority of cases, but where resistant strains are found or the child is seriously ill, co-trimoxazole, amoxicillin or ampicillin should be used.

Answer 123

Organism. Chlamydia trachomatis.

Answer 124

Clinical Features. Chlamydial infection presents as a urethritis in the male and as a cervical discharge in the female and is often indistinguishable from or present at the same time as gonorrhoea. The discharge can be purulent but is more likely to be mucoid with symptoms of burning on micturition. In the female, there may be oedema of the cervix and bleeding, but in 70% of sexually active women the infection is asymptomatic. This is a serious problem as it can lead to salpingitis and pelvic inflammatory disease. Asymptomatic males serve as carriers, spreading the infection, and are likely to become infertile due to the chlamydia killing sperm and decreasing their mobility.

Answer 125

Diagnosis may be indicated if N. gonorrhoeae cannot be found in the smear or culture of the discharge. It can be confirmed by the nucleic acid amplification test (NAAT), ligase chain reaction, enzyme immunoassay (EIA) or by direct immunofluorescence. A rapid test has been developed based on the recognition of lipopolysaccharide markers which gives results within 30 min. Either self-collected vaginal swabs can be used or else those obtained in clinics. A urine test is effective in men. Due to its ease and low cost, it is hoped that this method may become available for use in developing countries.

Answer 126

Transmission is by sexual intercourse, while contaminated hands can lead to conjunctival infection. Oral and anal intercourse are potent methods of transferring infection. Babies born to mothers with infection of their genital tract can develop chlamydia ophthalmia neonatorum. C. trachomatis is a risk factor for HIV infection in the female.

Answer 127

Period of Communicability. This is as long as active infection is present, which could be weeks to months in the undiagnosed case.

Answer 128

Occurrence and Distribution. Worldwide distribution among the sexually active. Probably one of the commonest STIs, but because it so often goes undiagnosed, the full burden of infection remains unknown. It is a considerable problem in Africa and South Asia.

Answer 129

Treatment is with azithromycin 1 g orally in a single dose, doxycycline 100 mg orally twice daily for 7 days, erythromycin 500 mg orally four times a day for 7 days or tetracycline 500 mg orally four times daily for 7 days. Sexual intercourse must be avoided until both partners are free of signs. Erythromycin is the recommended treatment if the patient is pregnant, but amoxycillin can also be used. All cases of gonorrhoea should be treated for chlamydia unless it has been confirmed to be absent by full laboratory tests.

Answer 130

Surveillance. Several sexually transmitted infections can occur together, so any discharge, urethritis or pelvic pain may indicate possible syphilis and gonorrhoea, which should always be looked for

Answer 131

Organism. Herpesvirus simplex type 1 (HSV-1); less commonly type 2 (HSV-2)

Answer 132

Clinical Features. Painful vesicles develop on the genitalia or surrounding area of both females and males, and these can subsequently ulcerate. Healing occurs after initial infection, only for the vesicles to recur at frequent intervals, often precipitated by stress or menstruation. Infection of the neonate can occur during delivery, resulting in encephalitis, liver damage or lesions in the eye, mouth or skin. Infection with HSV-2 carries an increased risk of developing HIV infection.

Answer 133

Diagnosis is made on clinical presentation and by scrapings of the lesions, in which characteristic multinucleated giant cells with intranuclear bodies are seen on microscopy. Confirmation can be made by fluorescence antibody testing, isolation of the virus or PCR.

Answer 134

Transmission is by sexual intercourse or direct contact, such as orogenital, or to the infant during delivery. HSV-2 used to be the main pathogen but this has now been replaced by more cases caused by HSV-1.

Answer 135

Occurrence and Distribution. A worldwide and increasing problem among the sexually active. As the infection is difficult to treat, there is a recurrent reservoir of infection with each clinical attack, and if one of these should occur during delivery, then neonatal death or disability will result. There is some suggestion that infection with HSV-1, normally as mouth ulcers in childhood, has some protective effect on acquiring HSV-2 infection. Decreasing natural infection of HSV-1 in many developed countries may help to explain the increase in HSV-2 infection

Answer 136

Control and Prevention. Infected persons should be warned of the increased risk of developing HIV infection. Several vaccines are under trial but the development of immunity is severely reduced in those persons with a previous infection of HSV-1

Answer 137

Treatment. There is no cure but acyclovir 200 mg orally five times daily for 7 days or acyclovir 400 mg orally three times a day for 7 days, or other analogues, will reduce the formation of new lesions, pain and the period of healing, but not recurrent attacks. Treatment can be given with each episode, helping to reduce the duration, the number of outbreaks and, possibly, viral shedding.

Answer 138

Surveillance. Any case of genital herpes should be tested for HIV infection

Answer 139

Organism. Human papillomavirus (HPV). There are many different types, with types 6–11 being associated with genital warts and types 16, 18, 31, 33 and 35 producing cervical dysplasia, which can lead to cancer of the cervix. Types 16 and 18 are responsible for 70% of cancer cases.

Answer 140

Clinical Features. The main clinical presentation is genital warts on the external genitalia or within the vagina, but a large proportion of infected persons show no clinical signs. When cellular immunity is depressed, condylomata acuminata, large fleshy growths in moist areas of the perineum, develop. However, the most serious consequence of HPV infection is the development of carcinoma, particularly of the cervix, but the anus and penis can also be involved. It is being more commonly recognized that oropharyngeal squamous cell carcinoma can develop from oral sex.

Answer 141

Diagnosis. Clinical diagnosis can be made if genital warts are present. Cervical smears stained by the Papanicolau method can detect precancerous changes and are routinely performed as a screening test in many countries.

Answer 142

Transmission is by sexual intercourse, but direct contact, as with other warts, is possible. Unprotected intercourse will lead to transmission of the oncogenic type 80% of the time.

Answer 143

Period of Communicability. Probably for a considerable period as cancer of the cervix appears to be associated with the cumulative number of sexual encounters.

Answer 144

Occurrence and Distribution. It has been estimated that between 9 and 13% of the world population is infected with HPV, which is some 630 million people. Some 70% of these infections are subclinical with only a proportion developing genital warts and some 28–40 million the pre-malignant condition. There are 0.5 million cases of cervical cancer every year in the world. The prevalence of chronic persistent infection is about 15% in developing countries and 7% in developed countries. Some 80% of the worldwide incidence of cervical cancer is in developing countries.

Answer 145

Control and Prevention. The usual methods of reducing STIs, such as delaying the age of first intercourse, monogamous relationships and the use of condoms, will all assist in decreasing the likelihood of developing HPV infection. The promotion of cervical smear testing in developed countries has allowed detection of precancer and early cervical cancer amenable to surgical treatment, but few if any developing countries are able to afford such a service. There are two vaccines to prevent HPV infection: a quadrivalent (HPV types 6, 11, 16 and 18) vaccine that can be given to girls from age 9 years and a bivalent (HPV types 16 and 18) vaccine that can be given to girls from age 10 years. The target population is girls of 9–13 years, and the vaccine is administered in two doses 6 months apart to girls under 15 and in three doses to women over 15. Protection lasts for at least 5 years, but programmes have not been running for long enough to decide when booster doses need to be given. The vaccine also provides some protection against anogenital warts in both females and males.

Answer 146

Treatment. Treatment of the warts is by cryotherapy, podophyllin, immune modulators (e.g. imiquod) or with trichloroacetic acid. Cone biopsy of the cervix can reduce the precancerous condition, but more extensive surgery will be required when cancer has develope

Answer 147

Surveillance. Cytological services for screening women at regular intervals have been shown to be cost-effective in reducing cervical cancer and should be set up wherever resources permit.

Answer 148

Organism. Human immunodeficiency virus (HIV), either type 1 (HIV-1) or type 2 (HIV-2), HIV-1 being more pathogenic

Answer 149

Clinical Features. HIV infection leads to a disruption of specific T-lymphocytes that bear the CD4 receptor (CD4+). This leads to a disruption of the cellmediated immune mechanisms, resulting in an increased susceptibility to opportunistic infections. The breakdown of the body’s defence system and the range of symptoms produced is called acquired immunodeficiency syndrome (AIDS). Presentation is generally by the symptoms of the opportunistic infection, so can be many and varied. Primary infection 2–4 weeks after exposure presents as an acute febrile illness, often with lymphadenopathy, pharyngitis, maculopapular rash, orogenital ulcers and meningoencephalitis. A transient lymphopenia may develop with low CD4 count. If the primary infection is mild or ignored, there follows a dormant period for several months, after which symptoms of an opportunistic infection occur. The opportunistic infections found are listed below under the account of clinical staging, with details of the sections (in parentheses) where more information will be found in the text. Any process that stresses the immune mechanism, such as repeat infections, will accelerate progression to AIDS. Tuberculosis (TB) and leprosy are affected by the disruption of the immune process. In any person with TB who contracts HIV, the infection will progress more rapidly, while tuberculoid leprosy cases can convert to lepromatous leprosy. It has been suspected that there is an interaction between HIV and malaria, and this has now been shown to be the case with almost 1 million excess malaria cases and 8500 excess HIV cases since the HIV epidemic first started in 2006 in just one district of Kenya.

Answer 150

Period of Communicability. Infectiousness is highest during initial infection, probably extending throughout the life of the individual, and increasing again as immunity becomes suppressed. Other STIs, especially of the ulcerative kind, increase the likelihood of transmission. People treated with an effective antiviral therapy regime can achieve undetectable viral loads but the treatment has not been shown to completely eliminate the risk of transferring infection. Other precautionary measures should also be utilized.

Answer 151

Occurrence and Distribution. There is worldwide occurrence, with some 33 million people living with HIV in 2007. An estimated 4.1 million become newly infected with HIV each year and 2.8 million die from it. The worst affected area is sub-Saharan Africa, with South Africa showing no sign of any decline in its epidemic, whereas improvement has taken place in other parts of the continent. The considerable tragedy in Africa is that infection rates in young women are three times those in young men, indicating the gender inequality. Many women lack socio-economic independence, education and access to health information and health services, making it difficult for them to avoid exposure to the virus. Infection has now spread to most other parts of the world, with prevalence increasing in China, Indonesia, Papua New Guinea and Vietnam, and signs of outbreaks in Pakistan and Bangladesh. There are estimated to be 8.3 million people with HIV in Asia, two-thirds of them in India. The annual number of new HIV cases diagnosed continues to rise in Russia and the Ukraine, while the Caribbean remains the second most affected area in the world. In East Africa, initial spread of infection was along transport routes, with lorry drivers making use of local bar girls at each of their stops; this has tended to be a common method of spread in other countries as well. In South Africa, HIV infection was introduced into the mining communities, in which it spread rapidly via prostitutes. Sadly, many infections in developing countries have been caused by the use of poorly sterilized needles when people have attended clinics for other illnesses. Parts of South America and some Caribbean islands have very high incidence rates due to the general attitude towards promiscuity. A worrying trend has been the unchanged incidence in Western countries, despite the availability of antiretroviral therapy (ART). It appears that the availability of treatment is reducing the fear of infection and allowing more risky behaviour to take place. There has been a strong movement to increase the availability of ART in developing countries, although it is only reaching one in five people who need it. It is hoped that ART therapy will reduce the stigma of AIDS and allow preventive programmes to be more effective. Both preventive and treatment strategies need to proceed at the same time because viral shedding can still continue in the treated person. Four key populations have been identified for special attention as they tend to have higher rates of HIV than the general population, yet receive the least resources, these are: • sex workers; • men who have sex with men; • injecting drug users; and • prisoners. In many countries, it is a vicious circle, with sex workers and homosexuals being criminalized so that they end up in prison, where the situation only gets worse. Many sex workers, prisoners and men who have sex with men also inject drugs, doubling their risk of infection. HIV-1 is common in the Americas, Europe, Asia and Central and East Africa, whereas HIV-2 is found in West Africa or in people that acquired their infection there.

Answer 152

Control and Prevention. Methods of control and prevention are aimed at the three routes of transmission: sexual, via blood and perinatal. The search for a vaccine has been a major priority, using either a live attenuated vaccine or a live recombinant vaccine, but none has progressed beyond the trial stage. The problem with all the vaccine candidates so far developed is the rapid rate at which the HIV virus alters its antigenic make-up. So, until a vaccine has been developed, other control measures are required. To prevent sexual spread: • Limit the number of sexual partners, encouraging monogamous relationships. • Avoid sexual contact with persons at high risk, such as commercial sex workers, bisexuals and homosexuals. • Encourage male and female condom use with the addition of vaginal microbicides. • Encourage programmes to circumcise males in high incidence areas. • Provide adequate facilities for the detection and treatment of STIs. • HIV testing and counselling to be made available both at special counselling centres and general clinics. Patients presenting with infections that are more common with HIV are counselled and offered HIV testing (called opt-in testing). However, where more than 1% of antenatal women are HIV positive, WHO recommends ‘provider initiated HIV counselling and testing’, whereby all patients regardless of their presenting illness are tested unless they decline (opt-out testing). • General education for girls and sex education for both boys and girls. • Lifestyle training (how to say ‘no’). To prevent blood spread: • Screen all blood for transfusions. • Test donors before they give blood. • Only use blood transfusions when essential. • Discontinue paid blood donors. • Use disposable syringes, needles, giving sets, lancets, etc. or ensure they are properly sterilized. Single-use syringes prevent syringes being used again. • Injecting drug users should be discouraged from sharing equipment, preferably using needle exchange schemes. • Medical workers should wear gloves when dealing with possible infected blood, e.g. at delivery and in the laboratory. To prevent perinatal spread: • Encourage all mothers attending antenatal clinic to have an HIV test. • Advise HIV-infected pregnant women about the risk to their infants and themselves during and after pregnancy. • Promote good obstetric practice; reduce trauma and decide on the necessity of such procedures as artificial rupture of membranes and fetal scalp monitoring. Only cut the umbilical cord when it has stopped pulsating. • Give priority antiretroviral therapy to HIV-positive pregnant women and to the newborn infant. • Provide information on breastfeeding to allow each mother to decide on whether to breastfeed or artificially feed her newborn child. Caesarean section should not be encouraged in developing countries as the risk to the mother in subsequent pregnancies is considerably increased, but it might be the strategy of choice in developed countries. A similar dilemma is with breastfeeding, which is responsible for much of the neonatal transmission, but to encourage bottle-feeding and leave the child more likely to die from diarrhoea due to contaminated bottles is not sound practice. WHO recommends that no change should be made in the vaccination programme to mothers and children even though they may be infected with AIDS, except in the HIV-positive child, who should not be given BCG. There have been several trials of vaccines against HIV, the most recent having a vaccine efficacy of 31.2% with no significant impact on viral load or CD4 counts, but this could be the basis for the development of more effective candidates. AIDS is not spread by: • mosquitoes; • casual contact such as shaking hands, or lavatory seats; or • through food, water or the respiratory rout

Answer 153

Control Programmes. The main method of control is health promotion, and this should involve community leaders, religious organizations and non-governmental organizations (NGOs). Promotion can be to the general public to supply them with the correct information, or to specific groups. The most cost-effective health education will be to high-risk groups such as commercial sex workers, homosexuals and workers who are single or unaccompanied by their families. Promotion of condom use and making condoms available at both commercial and government outlets should be instigated. Thailand has had much success with its brothel-based 100% condom use, a model being tried in other countries. As already noted, criminalization of sex workers and homosexuals only drives the practice underground and efforts should be made to rehabilitate these people into ordinary society by a change in law if necessary. Peer distribution of condoms was found to be very effective in Mumbai in reaching these disadvantaged groups. Men who have sex with men often have sex with women as well, making these women more vulnerable to infection too, so programmes to reach them may need to be developed. Needle and syringe exchange programmes in a number of countries have helped reduce the risk of infection in drug users. Prisons have been termed ‘incubators of HIV’, yet they are captive audiences and so much more could be done to reach this highly vulnerable group. Girls should have the same opportunity foreducation as boys, with sex education an integral part of the school curriculum. Counselling and testing facilities need to be readily available, as well as programmes on mother-to-child transmission. Improved diagnosis and treatment facilities for STIs need to be made available, providing early and adequate treatment. Condoms can be dispensed at clinics, markets or at any suitable social marketing opportunity.

Answer 154

Treatment. Co-trimoxazole prophylaxis can be given to HIV-positive persons to prevent P. jiroveci pneumonia. Recent WHO guidelines recommend all persons infected with HIV, regardless of CD4 cell counts or WHO clinical stage, should receive treatment and recommend pre-exposure prophylaxis with ART for people at substantial risk of HIV infection. Treatment regimes must use a combination of drugs to prevent resistance from developing, generally two non-nucleoside reverse transcriptase inhibitors and a protease inhibitor, but each patient must be individually assessed. The following should be started on ART: • patients with TB and hepatitis B (HBV) co infection irrespective of CD4 count; • symptomatic persons (including pregnant women) with clinical stage 3 or 4, irrespective of CD4 count; and • asymptomatic or symptomatic persons (including pregnant women) with clinical stages 1 or 2 and with a CD4 count of less than 350. The following first-line treatment regimes can be used (although efavirenz should not be used in the first trimester of the pregnant woman: • zidovudine plus lamivudine plus efavirenz (or nevirapine); and • tenovir disoproxil fumerate plus lamivudine (emtricitabine) plus efavirenz (or nevirapine). (This regime to be used for HIV/HBV co-infection.) Second-line therapy will depend on the regime used in first-line therapy. People must be counselled before starting ART because missing as few as three doses in a month can result in a rise in viral load, the development of drug resistance and treatment failure. As with TB, a family member or friend should be chosen as a treatment supporter, ensuring that tablets are taken and that the person attends regularly for follow-up. The spouse or sexual partner is the ideal choice, as preventive methods, such as using a condom, must be maintained despite being on treatment. The supporter should come with the patient and be given information leaflets, treatment diaries and other aids to help in maintaining the patient’s regular attendance. Mobile phone numbers can be used to recall late attendees and pill counts made to check adherence. ART cards and registers should be used in a similar way to that in TB programmes. Self-testing programmes have shown that people are three times more likely to report that they have HIV and start antiretroviral therapy. This needs to be combined with home assessment and initiation of HIV care. All HIV-positive persons should be tuberculin skin tested for TB, and information on any active symptoms asked for. If the TB test is positive and/or there are no symptoms related to TB, isoniazid prophylaxis should be given for 6 months. Any opportunistic infection must receive specific treatment for the condition.

Answer 155

Surveillance. Voluntary testing of all persons should be made available at health facilities, but more active provider-initiated HIV testing should be encouraged when attending health facilities for other reasons. Numbers of newly diagnosed HIV-positive persons give an indication of the progress of the epidemic and are reported to WHO using the case definitions above. Population-based surveys have been conducted in a number of countries and give a more accurate picture of the prevalence

Answer 156

Organism. Hepatitis B virus (HBV)

Answer 157

Clinical Features. After an insidious onset, with anorexia, nausea and abdominal discomfort, dark urine is produced and jaundice develops, from which the majority of patients recover. The symptoms are more severe than with hepatitis A, and in a small proportion of cases, a chronic active disease develops in which low-grade infection continues with periods of jaundice alternating with remissions. Illness can continue for many years, invariably resulting in cirrhosis. In many parts of the developing world, HBV infection is common, but only about 30% of cases will show any symptoms, the severity of the disease being dose dependent. The disease is more serious in those over 40 years old, in pregnant women and newborn infants. Hepatocellular carcinoma is associated with chronic HBV infection.

Answer 158

Diagnosis can be made by finding the surface antigens (HBsAg). There are four subtypes, adr, adw, ayr and ayw, which vary in their geographical distribution and so provide useful epidemiological markers. Several simple test kits for HBsAg are available, and consist of a small strip with a well at one end for the blood sample and the result read as a positive band or dot. A further antigen e (HBeAg) is a marker of increased infectivity as well as indicating active viral replication in hepatocytes (which may result in liver damage). PCR can be used to measure the viral load.

Answer 159

Transmission can occur from blood, serum, saliva and seminal fluid. It is a hazard of blood transfusions, renal dialysis, injections and tattooing. It can be transmitted by sexual intercourse and during delivery. In the developing world, most infections arise from the infected mother to her child during delivery, or in the reuse or poor sterilization of syringes and needles. HBV is 50–100 times more infectious than HIV. The virus has been found in some bloodsucking insects (e.g. bedbugs) but transmission by this means has not been shown to occur. Certain people with HBV are more infectious than others, resulting in a carrier state, the period of communicability being considerable. The risk of an infant becoming infected from a carrier mother can be 50–70% in some ethnic groups. There is a greater likelihood of the mother passing on the infection if she has acute HBV in the second or third trimester or up to 2 months after delivery. A high titre of the surface e antigen or a history of transmission to previous children increases the risk of a mother infecting her infant. The carrier state is more common in males and in those who acquired their infection in childhood.

Answer 160

Period of Communicability is from several weeks before the onset of symptoms until the end of clinical disease, unless the person becomes a carrier, in which case it is lifelong.

Answer 161

Occurrence and Distribution. The carrier state has been estimated to be present in over 350 million people, with varying rates in different parts of the world: Western Europe 1%, South and Central America 2–7%, and Africa, Asia and the Western Pacific more than 8%. Infection occurs commonly in infancy or early childhood in the more endemic areas, with young children more likely to develop chronic infection. The disease kills about 600,000 persons annually, but once there is a good vaccination status in the general population this can be expected to decline rapidly. HBV is an occupational hazard of health professionals so they should all be vaccinated, as well as taking precautions against contact with blood and body fluids, by the routine wearing of gloves.

Answer 162

Control and Prevention. HBV vaccine should be given to all children as soon after birth as possible, then either a second dose with the first DTP (diphtheria, tetanus, pertussis vaccine) and a third with the third DTP or a dose with each DTP. Immunity is thought to last for at least 15 years in the fully vaccinated. There is convincing evidence that reduction of carriers will prevent the development of primary liver cell cancer. Preventive methods are strict aseptic precautions in giving blood transfusions, injections and the handling of blood. All blood donors should be screened, with contributions to pooled blood being particularly scrutinized. The control of sexually transmitted infections has been covered above. Homosexual practice is particularly liable to lead to HBV infection. Persons at risk should be vaccinated.

Answer 163

Treatment. There is no specific treatment, but alpha-interferon and lamivudine have a limited effect in some people, particularly in the early stage of infection. Long-lasting PEGylated interferon is now mainly used. Its expense rules out its use in the majority of peopl

Answer 164

Surveillance. Blood obtained in antenatal clinics, STI clinics or for other purposes can be anonymously tested for HBsAg. Surveys in developing countries have demonstrated high levels of carriers, so by implementing routine vaccination follow-up surveys the effectiveness of the vaccination programme can be monitored.

Answer 165

Organism. Hepatitis C virus (HCV). There are many types of the virus, type 1 being the most serious.

Answer 166

Clinical Features. Similar in many respects to HBV, HCV produces a milder disease, but as many as 10–20% will progress to cirrhosis and 1–5% to liver cancer over a period of 20–30 years

Answer 167

Diagnosis is by EIA to detect HCV-specific antibodies, with confirmation by HCV recombinant immunoblot (RIBA) assay and HCV RNA testing. PCR is now commonly used. Simple screening tests are available that are similar to those for HBV, many of them manufactured in developing countries. When a diagnosis is made, it should be confirmed by a more sensitive test.

Answer 168

Transmission is due to the use of poorly sterilized needles, giving sets and other methods of parental administration, so is common in developing countries and in those that abuse drugs in developed countries. Sexual or perinatal transmission probably occurs only rarely.

Answer 169

Period of Communicability. Weeks before the start of clinical symptoms to lifelong

Answer 170

Occurrence and Distribution. Infection is found worldwide in the general population in developing countries, and mainly in drug users sharing equipment in the developed countries. However, there are probably many more cases than present figures suggest, and WHO estimates that there are 200 million infected, 3% of the world’s population. This means that there are about 170 million chronic carriers who could go on to develop cirrhosis or liver cancer. Some 3–4 million persons are newly infected each year. The worst affected regions are Africa with 5.3% prevalence, Eastern Mediterranean with 4.6% and the Western Pacific with 3.9%.

Answer 171

Control and Prevention. There is no vaccine for HCV so all precautions need to be taken to prevent further spread by rigorous adherence to the sterilization of needles and instruments, and the use of blood screened for HCV in transfusions. Needle and syringe exchange facilities should be made available for injecting drug users. HBA and HBV vaccinations should be given to prevent co-infection, thereby protecting the liver from further damage

Answer 172

Treatment. A combination of PEGylated interferon plus ribavirin will prevent the virus from causing further liver damage but may not cure the disease completely. Much depends on the type of virus, with type 1 particularly hard to treat. A new approach using a combination of two hepatitis C drugs, ledipasvir and sefosbuvir (called Harvoni in their combined form), interferes with the enzyme required by the virus to multiply, and has produced high cure rates.

Answer 173

Surveillance. HCV is often diagnosed as a result of the person feeling lethargic and having symptoms of liver damage without jaundice. In certain communities, such as high prevalence areas in developing countries and among drug abusers, it may be worth conducting surveys.

Answer 174

Organism. Virus of the Filoviridae group of organisms, with four distinct subtypes; Zaire, Sudan, Côte d’Ivoire and Reston.

Answer 175

Clinical Features. Illness presents with sudden onset of fever, headache, muscle pains, sore throat and profound weakness. This progresses to vomiting, diarrhoea and signs of internal and external bleeding, with (generally) liver and kidney damage. Mortality is 50–90%. The Ebola Reston subtype found in the Western Pacific causes asymptomatic illness.

Answer 176

Diagnosis is by ELISA for specific IgG and IgM antibodies, or by PCR, but should only be carried out in laboratories with maximum facilities for protecting staff. New tests on saliva and urine provide a safer method of making a diagnosis. A 15-min test is currently being tried in Guinea. Virus culture and subspecies identification is useful in identifying specific outbreaks.

Answer 177

Transmission is by person-to-person contact via blood, secretions, semen or tissues of an infected person. Infected blood, especially via syringes, causes the most serious infections, while transmission has occurred via semen up to 7 weeks after clinical recovery. Breast milk can also transmit infection and the breastfeeding mother will need to be counselled on whether to continue breastfeeding. Fruit bats of the family Pteropoditae have been found to carry the filovirus, and infection can occur from direct contact with bats, or possibly from their excreta. Several caves in sub-Saharan Africa have been found to harbour bats carrying the virus, so should be avoided. The killing and eating of bats is probably the way several epidemics have started. This suggests that Ebola may be a zoonosis, with indigenous people acquiring some immunity from contact with the virus at an early age, but the link has not been sufficiently established. Infection has also occurred through handling ill or dead chimpanzees, gorillas and forest antelopes. The Ebola Reston strain has been contracted through handling cynomolgus monkeys (crab-eating macaques).

Answer 178

Period of Communicability. From the start of symptoms, and for up to 10 weeks for seminal fluid. Health-care workers are particularly liable to become infected, especially during the phase of vomiting and diarrhoea. Contact with blood is invariably fatal.

Answer 179

Occurrence and Distribution. The main focus of infection is the rainforest of Central Africa, outbreaks having occurred in Sudan, Democratic Republic of Congo (DRC), where the first epidemic occurred (near the Ebola river), South Sudan, Gabon, Côte d’Ivoire and Uganda. The recent outbreak (2014–2015) centred on Liberia, Sierra Leone and Guinea, where it is thought to have started in a child eating a bat they had caught in the forest. It then spread rapidly in the non-immune population by person-to-person spread. By June 2015 it was estimated that there had been 27,000 cases and 11,000 deaths. Another focus of an Ebola-related virus has been found in monkeys in the Philippines exported for experimental purposes. This focal nature (again) suggests a zoonosis, but despite extensive search no reservoir has been found. Bats have been infected experimentally, but do not die from the disease, so might be responsible for maintaining the virus in the wild.

Answer 180

Control and Prevention. The strictest level of barrier nursing is required, taking particular care to avoid contact with blood and all secretions. Soiled clothes and bed linen must be disposed of properly as they can also spread infection. Patients that die must be buried or cremated immediately using the same precautions, relatives being forbidden to touch or take the body away for burial. Patients that recover must be counselled about the dangers of sexual intercourse and the infective nature of semen. All contacts of a case and accidental contacts by health-care workers must be quarantined and the temperature checked twice a day. Surveillance should continue for 3 weeks from the date of contact. Caves known to be inhabited by fruit bats in sub-Saharan Africa should be avoided. The killing and eating of fruit bats should be discouraged. Two vaccines, ChAd3-EBO-2 and VSV-ZEBOV, have shown good effectiveness in initial trials in the West Africa epidemic area.

Answer 181

Surveillance. Outbreaks should be reported to WHO, neighbouring countries and those with air connections, so that surveillance can be mounted on travellers. In view of the recent serious epidemic, it is proposed that rapid response teams should be on standby to investigate any future outbreaks and institute emergency control methods.

Answer 182

Organism. Dengue virus has four serotypes (1, 2, 3 and 4).

Answer 183

Clinical features. Dengue presents as a sudden onset of fever, retro-orbital headache, joint and muscle pains, and facial signs of flushing, puffy eyelids and red eyes. A maculopapular or scarlatina-form rash usually appears after 3–4 days. Depression and prolonged fatigue often occur following the acute manifestations. Dengue haemorrhagic fever (DHF; recently designated severe dengue), in which there is profound bleeding into skin and tissues, is now a serious feature of many epidemics. After the initial symptoms, the condition suddenly worsens with facial pallor, abdominal pain and cyanosis. The liver may become enlarged and then signs of bleeding occur, such as into the gastrointestinal tract, with concurrent shock. DHF is probably due to a sensitization with a previous dengue serotype, either acquired at birth or from a previous infection, type 2 being the most potent and types 3, 4 and 1 being responsible in decreasing importance. Differential effects on racial groups suggest that host factors may also have a role, as does the geographical origin of the dengue strain.

Answer 184

Clinical features. Dengue presents as a sudden onset of fever, retro-orbital headache, joint and muscle pains, and facial signs of flushing, puffy eyelids and red eyes. A maculopapular or scarlatina-form rash usually appears after 3–4 days. Depression and prolonged fatigue often occur following the acute manifestations. Dengue haemorrhagic fever (DHF; recently designated severe dengue), in which there is profound bleeding into skin and tissues, is now a serious feature of many epidemics. After the initial symptoms, the condition suddenly worsens with facial pallor, abdominal pain and cyanosis. The liver may become enlarged and then signs of bleeding occur, such as into the gastrointestinal tract, with concurrent shock. DHF is probably due to a sensitization with a previous dengue serotype, either acquired at birth or from a previous infection, type 2 being the most potent and types 3, 4 and 1 being responsible in decreasing importance. Differential effects on racial groups suggest that host factors may also have a role, as does the geographical origin of the dengue strain.

Answer 185

Diagnosis. Virus can be isolated from the blood in acute cases. IgM-capture ELISA on a single specimen indicates recent infection, which is confirmed by a rising titre in paired sera.

Answer 186

Transmission. Mosquitoes of the Aedes group, especially Ae. aegypti, Ae. albopictus or a member of the Ae. scutellaris group are responsible for transmission. These mosquitoes are more easily identifiable than most by their black colour, with distinctive white markings (Fig. 15.2). They like to breed close to humans, taking advantage of any water containers, old tyres, empty tins or other small collections of water in which they can breed. They are daytime biters and can be found in large numbers in urban and peri-urban areas. Ae. albopictus has comparatively recently become established in the USA, Central America and the Caribbean owing to the trade in used tyres. Virus is maintained in a human/mosquito cycle in many parts of the world, but in Africa and South-east Asia a monkey/mosquito cycle is involved.

Answer 187

Occurrence and distribution. Dengue is now endemic in South and Central America, sub-Saharan Africa and South and South-east Asia (Fig. 15.3). In more isolated communities, large epidemics have occurred, especially in island countries of the Caribbean and Pacific, with devastating effect. The epidemic can be so massive as to immobilize large segments of the population, disrupt the workforce and cause a breakdown in organization. The development of DHF has been variable, producing a number of deaths. It is estimated that there are about 50 million cases of dengue and 0.5 million of DHF, with 12,000 deaths due to dengue every year. Children are the main sufferers of both dengue and DHF

Answer 188

Control and prevention. The main method of control is to reduce mosquito breeding, especially of the Aedes mosquito, by depriving it of collections of water or covering them so that mosquitoes cannot enter. All water tanks, pots or other containers must be covered at all times, treating the covers with insecticides if there is not a perfect fit. Guttering around the roof can also allow pools of water to collect, so should be of sufficient slope for good drainage and be cleaned out regularly. Old tyres should have holes cut in them or be removed altogether (one answer to the disposal problem is to weight them and bury them at sea to form artificial reefs). People should check round their gardens and the immediate vicinity at regular intervals to remove any cans, coconut shells or other temporary collections of water. Children are very effective at doing this and can be encouraged with a marks or reward scheme. Screening of houses and mosquito nets are of little use because people are often outside their houses when the mosquito bites, but these measures are of value for young children. ULV spraying, either by fogging or by aircraft, is of value in the presence of an epidemic, but only adult mosquitoes are killed, which are soon replaced by young adults, unless simultaneous larval control is also in operation. A dengue vaccine is being tested, but there is concern that it may sensitize the individual and produce DHF.

Answer 189

Treatment. There is no specific treatment, but hypovolaemic shock must be treated with rapid fluid replacement and oxygen therapy.

Answer 190

Surveillance. Regular checks should be made on mosquito breeding, especially of Ae. aegypti. Samples are taken and the number of larvae breeding is counted to give an indication of the risk of transmission

Answer 191

Organism. The yellow fever virus is a flavivirus.

Answer 192

Clinical features. One of the haemorrhagic group of arbovirus infections, yellow fever presents with a sudden onset of fever, headache, backache, prostration and vomiting. Jaundice commences mildly at first and intensifies as the disease progresses. Albuminuria and leucopenia are found on examination, while the haemorrhagic symptoms of epistaxis, haematemesis, melaena and bleeding from the gums can all occur. In endemic areas, the fatality rate is low except in the non-indigenous. The death rate may reach 50% in epidemics.

Answer 193

Diagnosis is made on clinical grounds after initial identification of an outbreak. Virus can be isolated from blood in specialist laboratories, such as the Pasteur Institute in Dakar, and IgM tested by ELISA techniques. Viral isolation and typical liver histology from fatal human cases and in monkeys thought to have died from the disease can assist in the evaluation of epidemics. A revised case definition developed by WHO is: • Suspected, acute onset of fever, with jaundice appearing within 14 days. (See Table 8.2 for differential diagnosis of jaundice.) • Probable, presence of yellow fever IgM in the absence of yellow fever immunization within 30 days. Epidemiological link to a confirmed case or an outbreak. • Confirmed, detection of yellow-fever-specific IgM or fourfold increase of yellow fever IgM or IgG antibody titres or detection of yellow-fever-specific neutralizing antibodies in the absence of yellow fever immunization within 30 days. If no yellow fever immunization within 14 days, then either the detection of yellow fever virus genome in blood or other organs by PCR or of antigen in blood or other organs by immunoassay or the isolation of yellow fever virus.

Answer 194

Transmission. Yellow fever is a disease of the forest, maintained in the monkey population by the sylvatic transmission cycle, which involves Haemagogus, Sabethes and Aedes mosquitoes in America, and Aedes in Africa (Fig. 15.4). The monkeys are generally not affected by the disease but occasionally start dying, indicating that spread to the human population may soon begin. In South America, it may be a reduction in the monkey population that will make the canopy mosquito look for another blood meal and perhaps feed on humans. More commonly, it is the person who goes into the forest to cut wood or hunt that becomes bitten incidentally. When they return to their village or town, they are fed on by Ae. aegypti, and an urban yellow fever transmission cycle is set up (see Fig. 15.4). In Africa, three different kinds of mosquitoes are involved. Aedes africanus remains in the jungle canopy rarely feeding on humans, but should the monkey descend to the forest floor or even enter areas of human habitation, it is fed on by Aedes simpsoni, Aedes furcifer-taylori or Aedes luteocephalus. The mosquito then bites a person on the edge of the forest (the rural cycle), who returns to the village soon to suffer from yellow fever. Fed upon by the peridomestic mosquito Ae. aegypti, an urban cycle is started (Fig. 15.4). The extrinsic (within-mosquito) cycle of infection takes 5–30 days, depending on the temperature and type of mosquito. Transovarian (transovarial) infection can also occur.

Answer 195

Period of communicability is from before the fever commences to 5 days after, so the patient should be nursed under a mosquito net to prevent new mosquitoes from becoming infected.

Answer 196

Occurrence and distribution. Yellow fever nearly always presents as an epidemic in humans, affecting all ages and both sexes, although adults (particularly males) who go into the forest are likely to be the first to contract the disease. Yellow fever is restricted to the areas of Africa and South America shown in Fig. 5.1. WHO has established a special initiative to assist Benin, Burkina Faso, Cameroon, Côte d’Ivoire, Ghana, Guinea, Liberia, Mali, Nigeria, Senegal, Sierra Leone and Togo, the 12 highest risk countries (see further below).

Answer 197

Control and prevention. The most important part of the complex mosquito transmission cycle is Ae. aegypti. With its proximity to humans, it is capable of infecting a large number of people as well as being the easiest mosquito species to control. It breeds in small collections of water near to people’s houses, so a careful search for larvae and the destruction of breeding places can do much to reduce the danger. Simple clearance is the most effective method of reducing the mosquito population, but insecticides such as temephos (Abate) can be used where collections of water cannot be destroyed or covered. In the event of an epidemic, then emergency reduction by fogging or ULV spray from aircraft will rapidly destroy the adult population (but not the larvae). One attack of yellow fever confers immunity for life if the person survives the disease. Inapparent infections can also occur. A very effective vaccine has been developed, which provides immunity for at least 10 years and probably longer, so all those at risk in the known endemic areas should be vaccinated. This has been attempted by offering vaccination at markets and meetings, or systematically offering it to schoolchildren. WHO now recommend that yellow fever vaccination be included in the childhood vaccination programme in the 33 countries of Africa in the yellow fever zone; the vaccine is to be given at the same time as the measles vaccine. The countries of South America have already implemented childhood vaccination programmes. In the event of an epidemic, then ring vaccination can be performed; the epidemic is surrounded by a circle of vaccinated persons, progressively closing in on the centre of the outbreak. Areas of Africa and South America have been designated as yellow fever areas and all visitors to this zone require vaccination. If a person has visited a country where there is a risk of transmission and they are not vaccinated and then enter another country where the vector of yellow fever is present, then the authorities can quarantine that person for 6 days. In view of the rapid urbanization of African cities and the increase in migration, WHO is concerned that major outbreaks could occur, exhausting vaccine supplies, so is proposing to pre-emptively vaccinate some 48 million people (17% of the population) in the 12 high-risk countries. The priority groups for vaccination will be determined from the past history of yellow fever outbreaks in the particular district or its proximity to an outbreak, and the proportion of vaccinated persons in the district (the lower the proportion, the higher the priority). In order to do this, WHO has established a stockpile of vaccine that can be drawn on for preventive mass vaccination and emergency use. WHO now recommends that a single dose of yellow fever vaccine is sufficient to confer substantial immunity and life-long protection against yellow fever, and a booster dose of yellow fever vaccine is not needed. However, some countries might still require evidence of a booster every 10 years. From June 2016, life-long protection from a single vaccination will be accepted for certification purposes. In these days of rapid air transport, it has always been surprising that yellow fever has not been transported to Asia, where there are the vectors and conditions for transmission. A suggested reason is that there is some cross immunity with other Group B arboviruses (flaviviruses), and that the level of such induced immunity may be sufficient to prevent epidemic spread. A precaution is to spray all aircraft coming from a yellow fever area.

Answer 198

Treatment. There is no specific treatment, but supportive therapy is given to combat shock and renal failure.

Answer 199

Surveillance. All cases of suspected or confirmed yellow fever should be reported to WHO as an event of international public health importance. The prevalence of the urban vector can be measured by the Ae. aegypti index. This is the number of houses found with Ae. aegypti breeding within a specified area of 100 houses. Alternatively, the Breteau index can be used, which is the number of containers in which larvae are found out of 100 samples. If this is kept below 5%, or preferably 1%, then the danger of an epidemic is minimized.

Answer 200

Organism. There are four human malaria parasites, Plasmodium falciparum, P. vivax, P. malariae and P. ovale. P. falciparum causes the most serious disease and is the commonest parasite in tropical regions, but differs from P. vivax and P. ovale in having no persistent stage (the hypnozoite) from which repeat blood-stage parasites are produced. P. vivax has the widest geographical range, being found in temperate and subtropical zones as well as in the tropics. P. vivax infection will lead to relapses if a schizontocidal drug only is used for treatment, and some strains, e.g. the Chesson strain in New Guinea and Solomon Islands, require a more prolonged radical treatment. P. malariae produces a milder infection but is distinguished from the fever caused by the other three species by having paroxysms of fever every fourth day. P. malariae can persist as an asymptomatic low-grade parasitaemia for many years, to multiply at a future date as a clinical infection. P. ovale is the rarest of the parasites and is suppressed by infections with the other species. A few cases of malaria have been found to be due to P. knowlesi, which normally infects monkeys in South-east Asia. The malaria parasite Plasmodium may be the cause of one of the oldest parasitic infections of humans, dating from at least 60 million years ago when it inhabited the guts of reptiles. The parasite was transferred to bird and mammalian predators where forms evolved that entered the bloodstream. At some time, it adapted to the mosquito, with separate species evolving to parasitize different kinds of birds and mammals, including humans. While most species of Plasmodium are considered to have arisen in Africa, P. vivax was thought to have originated in Asia due to its genetic similarity to the species infecting Asian macaques; however, a closer link has now been found with chimps and gorillas, confirming its African origin. The malaria parasite reproduces asexually in the human and sexually in the mosquito. A merozoite attacks a red blood cell (RBC), divides asexually, rupturing the cell, and each newly formed merozoite attacks another RBC. Toxins are liberated when the cell ruptures, producing the clinical paroxysms. After several asexual cycles, male and female gametes (gametocytes) are produced, which are ingested when a mosquito takes a blood meal. These go through a complex developmental cycle in the stomach wall of the mosquito, culminating in the production of sporozoites, which migrate to the salivary glands ready to enter another person when the mosquito next takes a blood meal. The sporozoite enters a human liver cell, in which development to a schizont takes place. This ruptures, liberating merozoites, which attack RBCs, so starting an erythrocytic cycle all over again. In P. vivax and P. ovale, a persistent liver stage, the hypnozoite, is formed, meaning that if parasites are cleared from the blood, relapses can occur, often continuing for many years unless radical treatment is given.

Answer 201

Clinical features. Infection commences with fever and headache, soon developing into an alternating pattern of peaks of fever followed by sweating and profound chills. Classically, these take on a pattern of either 3 days (tertiary malaria) or 4 days (quaternary malaria). However, falciparum malaria can present in many different forms, including cerebral malaria (encephalopathy and coma), and acute shock, haematuria (blackwater fever) and jaundice. The higher the parasitaemia, the more severe the morbidity and the higher the mortality. Cerebral malaria in children presents as febrile seizures, making it difficult to differentiate it from other causes, but malaria should be considered the most likely diagnosis and treatment started without delay. Partial treatment leads to recrudescences of fever, whereas relapses can occur many years after initial infection with P. vivax and P. ovale. Interaction between malaria and HIV infection has now been shown to produce more severe clinical disease in persons already infected with human immunodeficiency virus (HIV), as well as an excess of cases

Answer 202

Diagnosis is from a thick blood smear (to detect parasites) and a thin smear (to determine species) (Fig. 15.6). Rapid diagnostic test (RDT) dipstick methods have made the diagnosis of malaria simpler, but need to be evaluated for each country in which they are to be used. They are particularly useful for surveys.

Answer 203

Transmission is by Anopheles mosquitoes (Table 15.2). The efficiency of the vector will depend on the species of Anopheles, its feeding habits and the environmental conditions. This varies widely, from A. gambiae, the most efficient of all malaria vectors, to a species such as A. culicifacies, which is comparatively inefficient. Vector efficiency is determined by a number of factors, such as the preferred food source (human or animal), the time of biting (easier in the middle of the night when people are sleeping) and whether the mosquito lives inside the house or outside; but the most important factor is the mosquito’s length of life. Only a few A. culicifacies will survive longer than 12 days and so become infective (i.e. most die before completion of the extrinsic cycle), whereas 50% of a population of A. gambiae will live longer than 12 days. Longer-living mosquitoes are better vectors. A female mosquito must have a blood meal before it can complete its gonotrophic cycle and lay a batch of eggs. The gonotrophic cycle is normally about 2–3 days but varies with temperature, species and locality. Long-living mosquitoes will be able to lay several batches of eggs, and this characteristic is used to estimate longevity of a mosquito species. Another factor is mosquito density. A large number of mosquitoes have a greater transmission potential than a few. Some mosquitoes are produced in large numbers at certain favourable times of the year, while others maintain more constant populations. The environment largely determines mosquito density. The most important environmental factors are temperature and humidity, with wind, phases of the moon and human activity having lesser effects. Temperature determines the length of the development cycle of the parasite and the survival of the mosquito vector. This means that in temperate climates malaria can only be transmitted in brief periods of warm weather when the right conditions are available. In tropical regions, altitude alters the temperature, and highland areas will have less (although possibly epidemic) malaria. Water is essential for the mosquito to breed. In arid desert countries, the mosquito cannot survive, but wells and irrigation have allowed mosquitoes to breed and malaria to appear. Rainfall generally increases the number of breeding places for mosquitoes, so there is more malaria in the wet season. However, the rain may be so great as to wash out breeding places, thereby instead producing a decrease in the population. The mosquito, being a fragile flyer, is easily blown by the wind, sometimes to its advantage, but generally to its disadvantage. On windy evenings, mosquito biting may decrease considerably. Nocturnal mosquitoes are sensitive to light, so on a moonlit night there is a reduction in numbers. Measurements of mosquito density must be made on several nights, or ideally over a period of months. Where the mosquito species is mainly zoophilic (feeds on animals), keeping domestic animals in proximity to the household will encourage mosquitoes to feed on them instead of on the human occupants. It is these environmental factors that determine whether malaria is endemic or epidemic. Where conditions of temperature and moisture permit all-year-round breeding of mosquitoes, then endemic malaria occurs, but if there is a marked dry season or reduction in temperature, then conditions for transmission may only be suitable during part of the year, resulting in seasonal malaria. If conditions are marginal and only favourable every few years, then epidemic malaria can result. Epidemic malaria is devastating as large numbers of people who have no immunity are attacked. Endemic and epidemic malaria call for quite different strategies of control. Malaria can also be transmitted by blood transfusion, from needles and syringes and rarely congenitally

Answer 204

Incubation period depends on the species and strain of the parasite

Answer 205

Period of communicability is as long as there are infective mosquitoes. For a mosquito to become infective it must live long enough for the parasite to complete the developmental cycle (the extrinsic cycle), which depends on the temperature and species. P. vivax completes this more quickly than P. falciparum. At 19°C, P. falciparum takes in excess of 30 days (beyond the life expectancy of the average mosquito), whereas P. vivax can still complete its cycle in less than 20 days; 17°C is the absolute minimum temperature for P. vivax, but the extrinsic cycle is longer than the lifetime of the mosquito.

Answer 206

Occurrence and distribution. In a non-immune population, children and adults of both sexes are affected equally. In areas of continuous infection with P. falciparum, malaria is predominantly an infection of children, in whom mortality can be considerable. The survivors acquire immunity, which is only preserved by the maintenance of parasites in the body, due to reinfection. Should the individual leave an area of continuous malaria, immunity may be reduced. The other time when immunity is reduced is during pregnancy, and severe malaria can occur in the pregnant woman, even one that has lived in an endemic area. This is worse in the first pregnancy than subsequently. The body responds to malaria by an enlargement of the spleen. The degree of enlargement and the proportion of the population with palpable spleens has been used as a measure of malarial endemicity: • Hypoendemic. Spleen rate in children (2–9 years) not exceeding 10%. • Mesoendemic. Spleen rate in children between 11 and 50%. • Hyperendemic. Spleen rate in children constantly over 50%. Spleen rate in adults also high (over 25%). • Holoendemic. Spleen rate in children constantly over 75%, but spleen rate in adults low. In endemic areas, the gametocyte rate is highest in the very young, but in epidemic malaria or areas where transmission has been considerably reduced, gametocytes occur at all ages. Malaria is found in the tropics and subtropics of the world, mostly P. falciparum, but P. vivax is the predominant species in the Indian subcontinent. The disease used to be more extensive, with seasonal malaria in temperate regions, but extensive control programmes have confined it to its present limits. However, increase in population and the development of resistance, both by the parasite and the mosquito, means that malaria is still the most important parasitic disease in the world. Control methods, especially the use of insecticide-treated mosquito nets, have recently brought down the number of cases from some 300 million and over 1 million deaths each year, to 214 million cases and 438,000 deaths in 2015. Unfortunately, an interaction between HIV infection and malaria has meant that HIV-infected people are more likely to contract malaria and to die from it. Certain genetic traits such as sickle cell anaemia and the Duffy minus mutation offer protection from malaria in Africa, particularly in West Africa where these conditions are more common. A similar effect is produced by alpha thalassaemia found in Papua New Guinea and Irian Jaya (part of Indonesia). Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is more widespread, but reaction with primaquine in the radical treatment of P. vivax can cause severe drug reactions. Global climatic change has resulted in an increase in epidemic malaria (infecting new or infrequently involved areas), and in the development of endemic malaria in highland areas which were normally protected by their lower temperatures

Answer 207

Control and prevention. Mathematical models were introduced in Section 2.4, malaria being one of the best examples in which they can be used to work out the strategy for control. The parasite life cycle was described above, while each of these stages can be represented mathematically on a diagram. The stages for each of the places where the life cycle can be interrupted are: 1. In humans: • Reduction of the duration of infection by chemotherapy. • Prevention of infections with gametocytes by chemoprophylaxis and vaccination. 2. In mosquitoes: • Prevention of human biting by personal protection and mosquito nets. • Decreasing mosquito density with larviciding and biological control. • Reduction of the proportion surviving to infectivity by residual insecticides and treated mosquito nets. • Reduction of the mosquito expectation of life by knock-down and residual insecticides

Answer 208

Personal protection items include clothing, mosquito nets and repellents. Items of clothing such as socks and shawls can be treated with repellents, which retain activity for some time, or repellents can be applied directly to the skin. Some naturally occurring plants have repellent properties, such as Tegetes minuta in East Africa. Mosquito nets are most effective if used properly. Providing subsidized mosquito nets can be used as a method of malaria control, especially for mothers and children who are liable to go to bed early (before mosquito biting starts). This can be improved by treating the nets with synthetic pyrethroid insecticides (such as permethrin, deltamethrin, alpha-cypermethrin or lambda-cyhalothrin). This repels mosquitoes and kills those that come into contact with the net. When used on a community scale, the concentration of insecticide-treated mosquito nets (ITNs) can produce a mass effect, reducing the mosquito population and the sporozoite rate. An improved technology is the manufacture of mosquito nets with the insecticide already in the net, known as long-lasting insecticidal nets (LLINs). These retain activity for at least 4 years, which avoids the regular retreating of nets, and are now the main method of malaria control. Mosquito bed nets are more effective and cheaper to maintain than screening the whole house, which is only recommended for people with a high standard of living. A small hole in the netting can render the rest ineffective. A knock-down spray can be used to kill mosquitoes that have entered a screened house. The use of smoke from mosquito coils or vaporizing mats can be surprisingly effective and has the advantage that it is a cheap personal protection. Coils are easily manufactured locally and naturally occurring substances, such as incorporated pyrethrum. People often sit around fires in the evening and by the addition of certain plants a repellent smoke can be produced. Mosquitoes can be encouraged to bite other animals if they are the preferred blood meal; however, if the animals are taken away, such as to market, then the mosquitoes may be forced to take their blood meals on humans. The habits of the malaria vectors will need to be known before encouraging this practice. Residual insecticides. Residual insecticides are applied to the inside surface of houses so that the resting mosquito (after it has taken its blood meal), absorbs a lethal dose of insecticide and dies before the parasites it has taken up in the blood can complete development. This was the main method of the malaria eradication programmes used in many countries of the world. Unfortunately, insecticidal resistance, organizational breakdown and reluctance by people to have their houses sprayed resulted in an abandonment of the goal of eradication. This has been replaced by a policy of malaria control in which house spraying may be a component. Larviciding and biological control. The number of larvae determines the density of mosquitoes, so any method which reduces the larval numbers inadvertently reduces the potential number of adults. The larvae can be attacked by several different methods: • using insecticides and larvicidal substances; • modification of the environment; and • biological control. Larvicidal substances can be oils that spread over the water surface and asphyxiate the larvae or have insecticidal properties. The size and flow of the body of water will determine which is the preferred method to use. Modification of the environment by drainage or filling in is the most permanent and effective, but is an expensive undertaking. It is worth spending money on engineering methods in areas of dense population such as towns, while in rural areas much can be achieved by using self-help schemes. The considerable advantage of this method is that once done, it lasts for a long time, if not permanently, and in these days of resistant mosquitoes it is seen as an economic proposition in some circumstances. Biological control using fish or bacilli (Bacillus thuringiensis or Bacillus sphaericus) will reduce mosquito larvae to a certain extent, but a balance, as with much of nature, often results. Biological control can also be used directly against adults with the sterile male technique. This has not been successful with mosquitoes because of the very large numbers involved and their short period of life. Another method that is being considered is species competition, whereby a non-malarial mosquito from another part of the world is introduced to compete with the resident vector. This has not met with any great success. In epidemic malaria, using a fogging machine or ULV spray from aircraft can rapidly reduce adult mosquito density. This will cut short the epidemic by killing off flying adults, but needs to be repeated regularly as new adults will continually be produced from larvae that are not affected by the knock-down sprays. Chemoprophylaxis. Attempts to use chemoprophylaxis on a large scale for pregnant women and young children have not met with much success, except in areas of seasonal malaria chemoprophylaxis (SMC, see Section 18.2.9), but could be given to persons at particular risk, such as non-immune immigrants or migrant workers. Chloroquine 300 mg (two tablets) weekly can be used where chloroquine resistance is not a major problem, but local advice should be sought. It is preferable to give pregnant women and young children priority in the distribution of ITNs or LLINs, or to use chemoprophylaxis in combination with these. Reducing the number of gametocytes. Quinine, chloroquine and amodiaquine are active against the gametocytes of P. vivax and P. malariae, but not against the more important P. falciparum. Proguanil and pyrimethamine act on the development of gametocytes within the mosquito on all four Plasmodium parasites. Primaquine has a highly active and rapid action on gametocytes of all species, whether in the blood or mosquito, and is used in combination with treatment in the individual. It has also been proposed as a method of reducing the level of gametocytes within the population, but would require an almost perfect mass treatment, as well as consideration of the danger of toxicity(especially with glucose-6-phosphate dehydrogenase deficient individuals), so is not considered a suitable method of malaria control. Surprisingly, Viagra has been found to have an effect on the gamete by stiffening it, facilitating its destruction by the spleen. Any person found to have malaria should, where possible, be protected by a mosquito net so as not to infect new mosquitoes. This is a particularly important measure during eradication and control campaigns, especially when endemicity is brought to a low level. Vaccines. Attempts to produce a vaccine against malaria have been in progress since 1910. A vaccine made from killed sporozoites by irradiating mosquitoes is reasonably effective, but cannot be produced on a large scale. Easier to produce are vaccines made by isolating the DNA fragments of the circumsporozoite antigen and cloning them through bacteria or yeasts. This has allowed large quantities of pure antigen to be produced, and trials of candidate vaccines. RTS,S vaccine given to children in three doses plus a booster had a 36% efficacy, but there was an increased incidence of meningitis. Pilot implementation studies have started to reveal how best to use the vaccine. It could be added to but not replace existing methods of malaria prevention. One of the strategies suggested is, in areas of seasonal malaria where SMC is used, to reduce the quantity and length of chemoprophylaxis. However, even if a vaccine is used, there will still be all the problems of vaccination programmes, such as coverage, administrative difficulties and response of the public. Prospects for malaria control. Malaria attracts the wonder cure; first it was the eradication programme, now all hope is pinned on the vaccine, but the disease is more likely to be controlled by simple, non-dramatic methods, where care to detail is applied. It is the encouragement of simple protective methods that everybody can follow, like using ITNs (or LLINs), or community action to modify the environment to make it unsuitable for mosquitoes to breed. A multiplicity of simple methods, carried out by many responsible people, is likely to be more successful in the long term than more complex methods. WHO has initiated a malaria elimination programme and the United Arab Emirates was declared free of malaria in 2007, Morocco and Turkmenistan in 2010 and Armenia in 2011.

Answer 209

Treatment of the uncomplicated case of P. vivax, P. malariae and P. ovale malaria is with chloroquine: • 600 mg of chloroquine base as an initial dose, • 6 h later, 300 mg chloroquine base, • followed by 300 mg chloroquine base for 3 or more days. However, chloroquine-resistant P. vivax has been reported from the Western Pacific islands, including the island of New Guinea, as well as from Guyana in South America. P. falciparum is resistant to chloroquine and many other antimalarials, largely as a result of their indiscriminate use. The artemisinin group of compounds, especially artesunate, artemether and dihydroartemisinin, are mostly effective, and WHO recommends that they be used in combination with other antimalarials as an artemisinin combination therapy (ACT) to reduce the development of resistance. Unfortunately, the first cases of artimisinin-resistant malaria have appeared in Cambodia and Thailand, and a new genetic mutation in Africa indicates developing resistance to artemisinin and quinine. Intense efforts are being made to contain and eliminate these pockets of resistance before they spread more widely. In the main focus of resistance in Cambodia, atovaquone-proguanil is used to treat resistant cases. ACT still remains effective in most places and one of the following regimes can be used: • artemether/lumefantrine; • artesunate plus amodiaquine (in areas where the cure rate of amodiaquine monotherapy is greater than 80%); • artesunate plus sulfadoxine/pyrimethamine (in areas where the cure rate of sulfadoxine/pyrimethamine is greater than 80%); • artesunate plus mefloquine (insufficient safety data to recommend use in Africa); and • dihydroartemisin plus piperaquine. The addition of a single dose of primaquine (0.75 mg/kg body weight) will accelerate the removal of gametocytes, but care must be used in glucose-6- phosphate dehydrogenase deficiency areas. While the microscope slide is being read (in many situations it may need to be sent to a centre for confirmatory microscopy) and the health worker has excluded other possible causes of fever, then presumptive treatment can be given. This is with a full course of therapy, which can be discontinued if the slide result is negative. In P. vivax, chloroquine will only clear parasites from the blood, and to effect radical cure, primaquine is administered in a dose of 15 mg base daily for 14 days (except in the island of New Guinea and other Western Pacific Islands, where more prolonged treatment is required). Case finding and treatment is an effective control strategy where there is a low level of malaria, but it needs to be used in combination with other methods.

Answer 210

Surveillance. In all areas where malaria is found, a blood slide should be taken from anyone with a fever. Where attempts are being made to eradicate or reduce the level of malaria, then an active system of surveillance may be instituted. Where a control method is in operation, then regular checks should be made, such as the proportion of houses with ITNs and the number of people sleeping under them.

Answer 211

Organism. There are seven species of Leishmania and a number of subspecies: Visceral leishmaniasis: L. donovani (donovani) L. infantum (infantum, chagasi). Mucocutaneous: L. braziliensis (braziliensis, peruviana, guyanensis, panamensis) New world cutaneous: L. mexicana (mexicana, amazonensis, pifanoi, garnhami, venezuelensis) Old world cutaneous: L. major L. tropica (tropica, killicki) L. aethiopica The parasites are all transmitted by the bite of the sandfly and undergo the same simple life cycle. Promastigotes enter humans with the bite of the sandfly, change into amastigotes (Fig. 15.19) and are engulfed by macrophages. They multiply and finally rupture the cell, invading other macrophages. When the sandfly takes a blood meal, the amastigotes change into promastigotes. These multiply continuously so that the number produced can be so large as to block the foregut of the sandfly. When the insect next bites, it is forced to regurgitate promastigotes into the host before it can take a blood meal. In cutaneous leishmaniasis, the amastigotes remain at the site of introduction, contained by the macrophages of the skin. In visceral leishmaniasis, large mononuclear cells and polymorphonuclear leucocytes become invaded and subsequently carry the parasites to the viscera, especially the liver, spleen and bone marrow. The mucocutaneous form is intermediate, the parasite restricting its attack to the reticuloendothelial system of the mucus membranes of the mouth, nose and throat.