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Decisions about the administration of blood products are an integral aspect of caring for the injured patient. The per-spective on transfusion of homologous blood, once viewed as a routine and low-risk procedure, has shifted dramatically as a result of increased recognition and awareness of its poten¬tial risks, including transfusion-transmitted diseases (TID). Consideration of the specific indications for and potential benefits of transfusion, weighed against its potential risks, is essential in each individual decision about the type and quantity of blood products to be administered. A Consensus Development Conference sponsored by the U.S. National Institutes of Health in 1988 suggested that transfusions be administered for clearly defined indications, including the restoration of intravascular volume, restoration of oxygen carrying capacity, correction of coagulation abnormalities, and correction of granulocyte deficiencies. 1
Blood products remain a vital and limited resource. In¬creased awareness of the potential risks of TID has not re¬duced the number of transfused units of blood, which has re¬mained steady at over 14-million units of blood components
per year since 1986.2 Responsible utilization of this limited commodity is an additional factor mandating judicious trans-fusion therapy.
In this chapter we will discuss the types of blood prod¬ucts available and their characteristics. We will then outline a strategy for matching appropriate products with their spe¬cific indications.
AVAILABLE BLOOD PRODUCTS
The majority of blood is collected with anticoagulant and is rapidly separated into components, including packed red blood cells (PRBCs), platelets, plasma, cryoprecipitate, leukocytes, and more concentrated clotting factors. (Figure 12-1. Table 12-1). The separation of blood into components and improvements in the anticoagulant/preservation solu¬tions have significantly increased the storage life of blood and its products and the efficiency of utilization of these important resources.
TRANSFUSION THERAPY
Robert G. Mackersie, MO, FAGS
,Ideally, the therapeutic goals of allogeneic and autologous blood transfusions should represent an extension of the gen¬eral goals of resuscitation for the trauma patient: (1) restora¬tion of circulating blood volume, (2) restoration of oxygen¬carrying capacity and tissue perfusion, and (3) prevention of metabolic disturbances and complications (such as coagulopa¬thy, acidosis, and hypothermia) and the post-resuscitation in¬flammatory response syndromes. Blood transfusions continue to be an important adjunct to the treatment of both major injury and a variety of critical illnesses. In the last several years, however, largely because of ch_ in. hl.aod _1>;i.Wb and transfusion practices resulting from the acquired immuno-deficiency syndrome (AIDS) epidemic, transfusions of red cell mass and blood components (platelets and plasma) continue to decline. Despite these recent trends and improvements in plasma and blood substitutes (see Chapter 26), allogeneic and autologous blood and blood products continue to provide the best means of improving oxygen-carrying capacity and correcting deficits and coagulation.
STORED BLOOD PRODUCTS
The earliest reported attempt at blood transfusion was in 1667, when whole animal blood was transfused into a patient. The result was a dramatic hemolytic transfusion reaction, caus¬ing the practice to be abandoned until the early 1800s, when transfusion of women hemorrhaging as a result of childbirth was again attempted. Similar incompatibility problems fore¬stalled further progress until the discovery of ABO blood group types (fable 25-1). The subsequent development of anticoagulants, around the turn of the 20th century, permitted blood matching and preservation of donated blood for the first time. Further changes in transfusion therapy became possible when technologic developments allowed the separa¬tion of whole blood into cellular and noncellular components. The emphasis on component therapy, the most common form of transfusion today, started with several publications by the Office of Medical Applications of Research and the National Institutes of Health. The majority of donor blood collected in the United States is now separated into the red cell mass (with varying amounts of donor plasma), the platelet component, and the plasma component.
Component Procurement
A unit of full donor blood typically contains approximately 500 mL (450 mL of blood plus 50 to 60 mL of an anticoagulant preservative). Whole blood is most commonly separated into various components. Packed red blood cells (RBCs), with a
TABLE 12-1. SUMMARY CHART OF BLOOD COMPONENTS
Component Major Indications Action Special Precautions Rate of Infusion
Whole blood Symptomatic anemia with Restoration of Must be ABO indentical For massive loss, fast as
large volume deficit oxygen-carrying Labile coagulation factors patient can tolerate
capacity, restoration deteriorate within
of blood volume 24 hours after collection
Red blood cells (RBCs) Symptomatic anemia Restoration of Must be ABO compatible As patient can tolerate
oxygen-carrying but less than 4 hours
capacity
Red blood cells (RBCs), Symptomatic anemia, Restoration of Must be ABO compatible As patient can tolerate
leukocytes removed febrile reactions from oxygen-carrying but less than 4 hours
leukocyte antibodies capacity
Fresh frozen plasma (FFP) Deficit of labile and Source of labile and Should be ABO compatible Less than 4 hours
stable plasma stable plasma
coagulation factors factors
and thrombocytopenia
Cryoprecipitated Hemophilia A, Provides Factor VIII, Frequent repeat doses Less than 4 hours
anti hemophilia von Willebrand's disease, fibrinogen, may be necessary
factor (AHF) hypofibrinogenemia, von Willebrand factor,
Factor XIII deficiency Factor XIII
Platelets Bleeding from Improves hemostasis Should not use some micro- Less than 4 hours
(pheresis) thrombocytopenia or aggregate filters (check
platelet-function manufacturer's instruction)
abnormality
Granulocytes Neutropenia with infection Provides granulocytes Must be ABO compatible, One unit over 2-4 hour
(pheresis) do not use depth-type period; observe
microaggregate filters closely for reactions
What World Health Organisation says about Safety in Blood Transfusion
Blood transfusion is an essential part of modern health care. Used
correctly, it can save life and improve health. However, as with any
therapeutic intervention, it may result in acute or delayed
complications and carries the risk of transmission of infectious
agents, such as HIV, hepatitis viruses, syphilis and Chagas disease.
The inappropriate use of blood and blood products, coupled with the
transfusion of unscreened or improperly screened units, particularly
in countries with poor blood programmes, increases the risk of TTIs
to recipients. It also widen the gaps between supply and demands and
contributes to shortages of blood and blood products for patient
requiring transfusion. Thus, it is necessary to reduce the
unnecessary transfusions. This can be achieved through the
appropriate clinical use of blood, avoiding the needs for
transfusion and use of alternatives to transfusion. The transfusion
is deemed appropriate when it is used to treat condition leading to
significant morbidity and mortality that cannot be prevented or
managed effectively by other means. The commitment of the health
authorities, health care providers and clinicians are important in
prevention, early diagnosis and treatment of diseases/ conditions
that could lead to the need for blood transfusion.
Key elements of effective clinical use of blood
Consistently effective clinical transfusion practice cannot be
achieved unless the following elements are in place:
well organized blood programme, coordinated at national level to
guarantee safe, adequate and timely supply;
a national blood policy that addresses the clinical use of blood,
with appropriate supportive legal frameworks;
a national committee on the clinical use of blood and hospital
transfusion committees at local level to implement, regularly
review and update the national policy and guidelines;
national guidelines on the clinical use of blood to aid
prescribers of blood in their clinical decisions about
transfusion, based on systematic reviews of evidence on clinical
effectiveness. The development of these guidelines requires
involvement of blood prescribers from different clinical
disciplines working together with the blood transfusion services.
These guidelines should suit local situation;
the availability of simple alternatives for transfusion
(crystalloids and colloids) for the correction of hypovolaemia,
and pharmaceuticals and medical devices to reduce blood loss;
the education and training of clinician, nurses and blood
transfusion service staff involved in the transfusion process;
monitoring and evaluation of the implementation of the national
policy and guidelines and the use of monitoring data in quality
improvement and education programme to assist clinicians to
improve their practice.
Activities
In order to support Member States in developing systems for
appropriate use of blood and to reduce unnecessary transfusion, WHO
has produced a series of recommendations, guidelines and learning
materials, including Recommendations on Developing a National Policy
and Guidelines on the Clinical Use of Blood and a module of
interactive learning material, The Clinical Use of Blood.
The recommendations provide assistance to Member States in
developing and implementing national policies and guidelines and
ensuring active collaboration between the blood transfusion service
and clinicians throughout the management of patients who may require
transfusion. They emphasize the importance of education and training
in the clinical use of blood for all clinical and blood bank staff
involved in the transfusion process.
The learning material includes a comprehensive module that can be
used in undergraduate and postgraduate programmes, in-service
training and continuing medical education programmes or for
independent study by individual clinicians and blood transfusion
specialists, as well as a pocket handbook which summarizes the
information contained in the module and has been produced for quick
reference by clinicians who need to make urgent decisions on
transfusion.
The WHO- HQ in collaboration with the regional offices also has
carried out global and regional workshops on promotion of
appropriate clinical use of blood in the African, American, Eastern
Mediterranean and South East Asian Region as well as national
workshops in China and India. These promoted the development of
national policies and guidelines on transfusion, the establishment
of hospital transfusion committees and haemovigilance systems, the
incorporation of transfusion medicine into medical and nursing
school curricula and the development of education and training
programmes for physicians, nurses and other prescribers of blood.
WHO also provides country support in the development and
implementation of transfusion guidelines, the establishment of
hospital transfusion committees and the training of clinicians.
Related documents
:: Aide-Memoire on Clinical Use of Blood in English [pdf 144kb]
:: Aide-Memoire on Clinical Use of Blood in French [pdf 92kb]
:: The Clinical Use of Blood Handbook in English [pdf 717kb]
:: The Clinical Use of Blood Handbook in Portuguese [pdf 7.20Mb]
:: The Clinical Use of Blood Handbook in Spanish [pdf 5.91Mb]
:: The Clinical Use of Blood in Obstetrics, Paediatrics, Surgery &
Anaesthesia, Trauma & Burns. Module in English [pdf 1.62Mb]
:: The Clinical Use of Blood in Obstetrics, Paediatrics, Surgery &
Anaesthesia, Trauma & Burns. Module in Portuguese [pdf 12.53Mb]
:: The Clinical Use of Blood in Obstetrics, Paediatrics, Surgery &
Anaesthesia, Trauma & Burns. Module in Spanish [pdf 11.25Mb]
:: Recommendations on Developing a National Policy and Guidelines on
the Clinical Use of Blood in English [pdf 739kb]
:: Recommendations on Developing a National Policy and Guidelines on
the Clinical Use of Blood in Spanish [pdf 2.24Mb]
Recommendations on Developing a National Policy and Guidelines on
the Clinical Use of Blood
French [pdf 245kb]
Contact information
World Health Organization
Department of Essential Health Technologies
(HTP/EHT/BTS)
20 Avenue Appia
1211, Geneva 27
Switzerland
Tel: +41 22 791 4660
Fax: +41 22 791 4836
Email: bloodsafety@who.int
TYPHOID FEVER
Introduction
Typhoid or enteric fever is an ancient disease, which has afflicted mankind since human populations grew large enough to contaminate their water and food supplies. It is caused by Salmonella enterica serovar typhi (previously known as salmonella typhi), a pathogen specific only to humans, as well as by certain non-typhoid salmonella (NTS), particularly Paratyphoid strains A, B, C. These waterborne gram negative aerobes are associated with poor sanitation and fecal contamination of water and food supplies. The syndrome needs to be distinguished from that caused by many other organisms. Today there are as many as 16-30 million cases per year, almost exclusively in the developing world, with a mortality rate of 10%. Recent developments in the mapping of the Salmonella genome have provided insights into its pathogenicity and how antibiotic resistance and human immunity develop. Typhoid fever is important surgically because abdominal complications such as intestinal perforation, bleeding, cholecystitis and pancreatitis represent the most serious complications of the illness. Typhoid perforation of the ileum is one of the most common causes of bowel perforation in the developing world. (1) Excellent reviews are available for both adult (2-6) as well as pediatric disease. (7) This Review will focus on recent developments in our understanding of this disease.
History
Typhoid fever was not well understood in the ancient world, probably because its symptoms are not primarily diarrheal, but rather systemic and non-specific. It was only in the mid-19th century that physicians began to distinguish it from typhus and malaria. (8) Sir William Osler’s clinical description remains unsurpassed. Typhoid fever was frequently associated with military campaigns and was a significant cause of death in the American Civil War and Boer War where deaths from typhoid exceeded those from combat. (9) With recognition that fecal contamination of food and water supplies was the main mode of transmission of the illness and measures taken to prevent these (10;11), typhoid fever has been restricted, in industrialized countries, to localized epidemics (12;13) and infections in travelers returning from endemic areas. (14)
Epidemiology
In contrast to that seen in the rich countries, typhoid fever remains an important cause of illness in the developing world where annual incidences in Papua New Guinea and Indonesia may reach 1200/100,000 population. A recent epidemiologic study showed that south-east and south-central Asia are the regions of highest endemicity with rates greater than 100/100,000 cases per year; the rest of Asia, Africa, Latin America, the Caribbean and Oceania (except Australia and New Zealand) are the next highest with incidence rates of 10-100/100,000 and Europe, North America and the rest of the developed world have low rates of disease. (15) Typhoid fever represents the 4th most common cause of death in Pakistan. (16)
The majority of patients, 60-90%, are treated as outpatients and, therefore, hospital based studies will underestimate true incidence. Two hospital based case-control studies from Vietnam found that risk of infection was related to recent contact with an infected person, lack of education and drinking untreated water. (17;18) S. paratyphi A, which normally causes about 15-20% of cases of typhoid fever in Asia, increasingly is becoming a pathogen in India (19) and China (20), possibly due to vaccination against S. typhi. Recent epidemiologic studies also show the rise of multi-drug resistant (MDR) organisms. (21) In a study of 1100 hospitalized children in Pakistan, the mortality rate of 1.6% was found to be related to younger age and MDR infection. (22)
Traditionally the age range considered to be at greatest risk was 5-25 years. However this has been questioned in a study from a private laboratory in Bangladesh, which found that the 57% of S. typhi isolates were in children less than 5 years of age and 27% less than 2 years. (23) This has significant implications for vaccination policies.
Genetics
In 2001 the entire genome of a MDR isolate of S. typhi was sequenced. (24) This showed that Salmonella share more than 70-80% of genes with other enteric bacteria, like E. coli. Another feature of S. typhi genome is the presence of over 200 inactivated genes which are felt to be related to the adaptation of the bacteria to the human host and possibly its ability to invade human tissue. Drug resistance is encoded in a transmissible plasmid. The development of additional horizontal genes in the salmonella pathogenicity islands (SPI) represented the separation of the E. Coli and Salmonella lineages and allows for the targeting of intestinal epithelial cells by Salmonella. (25)
Pathogenesis
Much of the genetic and cellular studies on the pathophysiology of invasive Salmonella infection have been carried out in the murine model using S. typhimurium, which causes invasive disease in mice but not in humans. As opposed to the Salmonella spp. associated with human diarrheal illness, S. typhi and those strains that cause typhoid fever are able to achieve cellular invasion.
The pathophysiology of typhoid fever is a complex process which proceeds through several stages. (24;26;27) The disease begins with an asymptomatic incubation period of 7-14 days, (inversely related to the size of the infecting dose), during which bacteria invade macrophages and spread throughout the reticuloendothelial system. The first week of symptomatic disease is characterized by progressive elevation of the temperature followed by bacteremia. The second week begins with the development of rose spots, abdominal pain and splenomegaly. The third week is marked by a more intense intestinal inflammatory response particularly in the Peyer’s patches with associated necrosis which can result in perforation and hemorrhage. These clinical stages are associated with complex cellular events just now being understood.
First, ingested bacteria must survive the acidic environment of the stomach. The known increased risk of typhoid fever with concomitant Helicobacter pylori infection (28) may express itself via the hypochlorhydria associated with chronic H.pylori infection. (29) Invading organisms pass through the intestinal epithelial cells and come into contact with phagocytic cells in the Peyer’s patches of the intestinal wall. However the macrophages do not kill the bacteria. Thence, bacterial replication is primarily intracellular. Salmonella avoids encapsulation in lysosomes by diverting normal cellular mechanisms. (30) Bacteria inject effector proteins into the cells of the innate immune system (macrophages and natural killer cells) though a type III protein secretion system (TTSS) which stimulate both pro and anti-inflammatory responses. (31)
Over the asymptomatic incubation period of 7-14 days the bacteria proliferate and spread through the blood stream to other cells in the reticuloendothelial system in the liver, spleen, bone marrow and gall bladder. As replication inside phagocytic cells continues, bacteria are shed into the blood stream in sustained but low concentrations and the clinical syndrome of fever, headache and abdominal pain begins. The gallbladder is felt to be a significant site (32) for ongoing exposure of intestinal epithelial cells to the pathogen. The inflammatory response to this process of repeated exposure is felt to give rise to the necrosis which is a prominent feature of the disease. (33) This occurs in areas of greatest macrophage concentration such as the Peyer’s patches and explains why intestinal bleeding and perforation are the most frequent complications. Elsewhere typhoid nodules, foci of macrophages and lymphocytes proliferate. As the infection progresses the typical changes of sepsis accumulate in the heart, brain and kidneys. If not interrupted this process may lead to circulatory failure and death from overwhelming sepsis.
Prevention
Infected or asymptomatic carrier humans represent the reservoir for S. typhi. Therefore identification and treatment of these individuals represents one strategy for interruption of transmission.
Food and water sanitation
There is no doubt that lack of clean drinking water and unsanitary conditions for the production and preparation of food represent the main reasons for the ongoing endemicity of typhoid fever in the developing world. Poor water quality, sanitation and hygiene account for some 1.7 million deaths a year world-wide (3.1% of all deaths and 3.7% of all DALY's), mainly through infectious diarrhea. Nine out of 10 such deaths are in children. (34) Poverty, uncontrolled urbanization and inadequate infrastructure all contribute to the contamination of water supplies. (35) Filtration and chlorination together are effective methods of interrupting the transmission of water-borne diseases. (36;37)
Vaccine
The other approach to the control and eradication of typhoid fever has been through vaccination. Acquired immunity to S. typhi infection is both humoral and cellular but is incomplete, allowing for subsequent infections and restricting the efficacy of vaccines. (38;39) Older, parenteral whole-cell vaccines resulted in significant local and systemic reactions. (40) Two new vaccines are in current use: a parenteral capsule polysaccharide vaccine based on the Vi antigen and an oral live attenuated vaccine containing strain Ty21a. The first, while resulting in local pain in 86% of children, requires 1 injection with a booster in 3 years and confers protection within 7-10 days of inoculation. On the other hand the Ty21a vaccine requires several doses, is only moderately immunogenic and its efficacy is reduced by simultaneous anti-malarial therapy, (although a report from Gabon showed that simultaneous anti-malarial prophylaxis with atovaquone/proguanil does not have this effect (41)). A systematic review for the Cochrane Database showed these two vaccines had significantly reduced efficacy (efficacy rates approx.50%) in comparison to the older whole-cell vaccines, but fewer side effects.(42) Current vaccines do not afford protection against Paratyphoid strains. The search for better vaccines continues. (43)
The use of vaccines for travelers to endemic areas has been recommended for some time; (44) even if the travel is for short periods. (45) Malaria remains the most common febrile disease of returning travelers to Italy requiring hospital admission. (46)
Mass vaccination campaigns have been used to lower the risk of disease in India and Thailand, but their use in the rest of the developing world is otherwise limited. A report from the ongoing epidemic in Tajikistan advocated mass vaccination. (47) A recent report from an urban slum community in Delhi, India showed the high costs of typhoid fever and recommended more widespread vaccination. (48) The current Vi and Ty21a vaccines are not licensed for use in children less than 2 years, in whom its efficacy is unproven, and therefore are deemed unsuitable for expanded immunization programs which target infants in their first year of life. (49) They are also costly. All these factors have restricted mass vaccination for typhoid in endemic countries.
The World Health Organization appears to advocate mass vaccination in endemic areas. (50;51) However this is seldom implemented. The Diseases of the Most Impoverished (DOMI) project is undertaking a randomized cluster vaccination program in Asia which should help to clarify the effects of mass typhoid vaccination. (52)
Clinical Spectrum
Traditionally the age range considered at greatest risk is 5-25 years of age, although young children and infants may also be infected. In these the disease may present as a non-specific febrile illness until diagnostic tests are positive. Akpede from Nigeria provides an excellent review of the management of these cases, including those with HIV. (53)
After the initial 7-14 day asymptomatic phase, the clinical features of typhoid fever begin with the onset of a remitting diurnal fever, anorexia, headache, lethargy, confusion, cough and abdominal pain. (54) Constipation is considered a feature, although diarrhea and vomiting is recognized, particularly with young children and those infected with HIV. Relative bradycardia is said to be a feature; increased heart rate is correlated with later stages and with mortality. (55) The clinical signs are few: rose spots (pink macules which blanch on pressure, are present on the thorax and abdomen of 60% of light-skinned patients but are considerably more difficult to detect in dark-skinned patients); abdominal tenderness (acute abdomen if perforation); splenomegaly more common than hepatomegaly; rales (with a normal chest xray); conjunctivitis and apathy. Assessment of hemodynamic and mental status is important and correlates with severity of illness. In contrast to other investigators Haq et al. found clinical factors strongly correlated with diagnostic accuracy. (56)
Thielman gives a very good differential diagnosis of other infectious which may mimic typhoid fever. (3) In Africa, malaria is probably the most important disease from which typhoid must be distinguished. (57;58)
Non resolution gives rise to complications which are discussed below. Typhoid fever patients suffer a relapse rate of 5-10% and 1-3% will become asymptomatic carriers, potentially infecting others. Relapses take the form of a milder disease and are less common after quinolone therapy. Carriers excrete S. typhi in the stool more than 3 months after treatment. In Egypt, carrier state is associated with urinary pathology such as Schistosomiasis and may be evidenced by urinary excretion. (6) Carriers require treatment with high dose quinolones (ciprofloxacin 750mg q12h) for 4 weeks. Carrier state associated with cholelithiasis is a risk for gall bladder cancer and requires cholecystectomy. (59)
Diagnosis
The lack of specificity of the clinical spectrum, added to the difficulty of achieving a definitive bacteriologic or serologic diagnosis, frustrates clinicians managing typhoid fever.(60;61) Laboratory tests are non-specific but haemoglobin, white cell and platelet counts are usually reduced. Liver function tests are mildly elevated.
Culture of the infectious agent may be obtained from stool, urine, blood, bone marrow or bile. Bone marrow is the most sensitive source (80-95%) and positive blood cultures (60-80%) are facilitated by increasing the volume sampled. (62) Detection of S. typhi DNA by polymerase chain reaction (PCR) has recently been shown to be a very sensitive index of infection. (63)
Serologic tests have a long but limited history of use in typhoid fever. The Widal test, useful only for infection with S. typhi, detects O (surface) and H (flagellar) antigens. However, baseline titers in the general population must be determined for each geographic region. (64-66) When used as a single test in endemic areas, it lacks sensitivity and specificity. (67) A 4 fold rise in O, H or Vi titers provides support for the diagnosis of typhoid fever, but is not useful in the acute situation. As a result, numerous other serologic tests are being developed (2): ELISA; (68-70) salivary IgA;(71) a modified Widal test to detect IgM; (72) and dipstick assay.(73)
Treatment
It is recommended that treatment of typhoid fever begin on the basis of clinical findings prior to definitive diagnosis. Sadly in endemic regions, facilities for definitive diagnosis, based on blood or bone marrow culture or serologic tests may be entirely lacking. Supportive measures such as oral or intravenous rehydration, antipyretics, appropriate nutrition and blood transfusion are important.
Mortality from typhoid fever showed a marked decline from 20% to 1% after the introduction of chloramphenicol in 1948. (74) Chloramphenicol however does not prevent relapse unless given for 2-3 weeks; the carrier state is not eradicated; nor is it useful against MDR strains. (75) Ampicillin and sulfonamides, co-trimazole, became the next antibiotics to be used, but multi-drug resistant MDR organisms developed.(76-78) In some regions with high MDR prevalence, sensitivity to chloramphenicol has re-emerged. (79) MDR strains are noted to be more virulent and associated with increased mortality and complications.
The flouroquinolones - ofloxacin and ciprofloxacin, the third generation cephalosporins -ceftriazone and cefixime, and azithromycin, a macrolide antibiotic, are the drugs of choice for MDR typhoid fever. Flouroquinolones achieve excellent penetration in macrophages and bile, important sites of infection. In the developed countries they have been used infrequently in patients less than 18 years of age, because of potential arthropathy. However there is increased evidence for their safety in this population. However, resistance to flouroquinolones has also developed and represents a significant threat to the treatment of typhoid fever. (80) The presence of nalidixic acid resistance is a marker for decreased susceptibility to flouroquinolones and should be tested for when dealing with MDR strains.(81-83) Nalidixic acid resistant strains may show a slower response to flouroquinolones and require higher doses (ciprofloxacin 1500mg/d instead of 1000mg/d). Switching to ceftriaxone or azithromycin may be preferable in these patients. (84) These agents should be given for at least 7 days.
The standard duration of treatment has been for 10-14 days, but uncomplicated typhoid fever has been shown to respond to shorter courses of flouroquinolones, ie. 2-3 days of treatment.(85) Thaver (75), in a systematic review for the Cochrane database comparing flouroquinolones with other antibiotics, concluded that the scientific data derived from RCTs was poor, and that there was little to recommend flouroquinolones over 1st line drugs, (chloramphenicol, ampicillin and co-trimazole). Flouroquinolones reduced failure rates when compared to third generation cephalosporins. The study recommended large multi-center outpatient trials comparing flouroquinolones and 1st line therapy in children to settle this question. Thaver et al admit their conclusions differ from those of Parry (5) and standard textbooks which recommend flouroquinolones as modern 1st line therapy. (3;4)
Since there is great regional variability with regard to antibiotic sensitivity and the presence of MDR strains and because misuse of antibiotics is a potent cause of the development of MDR strains (86), it is essential that physicians working in regions where typhoid fever is endemic, ascertain the nature and prevalence of the different strains and base appropriate recommendations for first and second line therapy on this information.
The WHO recommends the following regimes for uncomplicated typhoid fever.
Table 1 page 20 (2)
In severe disease the following regimes are recommended. Table 2 page 23 (2)
Complications
Complications occur in 10-15% of patients, particularly those who have been ill for more than 2 weeks. Gastrointestinal hemorrhage, perforation and encephalopathy are the most important. GI hemorrhage is most common but usually resolves without surgery. Severe typhoid may be defined as occurring in those patients with hypotension despite rehydration and mental confusion or altered state of consciousness. These patients may benefit from high dose dexamethasone therapy (3mg/kg followed by 8 doses of 1mg/kg q6h) with a marked reduction in mortality. (87) This is one of the few instances where high dose steroids are of value in sepsis. (88)
Perforation
The surgeon is typically consulted in typhoid fever when perforation is suspected. It may present suddenly as an acute abdomen or more commonly as worsening in an already sick patient with increasing abdominal signs, rising pulse and falling blood pressure. (89) The presence of free air on abdominal xrays is pathognomonic.
These are very sick patients who require vigorous resuscitation and the addition of metronidazole to combat gram-negative anaerobes and gentamycin for aerobes. Conservative therapy has been abandoned with improved mortality rates. (90) Mortality increased when time to presentation is delayed and also with delayed time to surgery after perforation. (91) Mortality rates vary from 14% in Nigeria (89) to 34% in Cote d’Ivoire. (92) Single perforations are most common (70%) and in the terminal ileum, but multiple perforations may occur.(93)
At operation the entire small bowel and proximal colon should be carefully examined for perforation. Debate exists as to the various methods of closure from simple suture, to wedge resection and closure to segmental resection and primary anastomosis. (94;95) It is not clear to me that any conclusion can be drawn from the evidence. Obviously multiple perforations lend themselves to segmental resection.
Other complications
Numerous other complications are seen with typhoid fever. (4) see Table 163-1 The most important surgical ones being: hepatic or splenic abscess(96), splenic rupture (97) and pancreatitis. Encephalomyelitis (98), osteomyelitis (99), glomerulonephritis and renal failure (100) may all occur. Myocarditis is a common cause of circulatory collapse.
Conclusions
Despite intensive scrutiny and major advances in genetic research and understanding the details of cellular inflammation, typhoid fever remains a major cause of death and disease in the developing world. Its eradication awaits the provision of sanitary water supplies and proper disposal of human sewage. Its eradication would probably be accelerated by programs of mass vaccination in endemic regions. Appropriate antibiotic therapy may postpone the further development of MDR strains. In the meantime, surgeons will continue to be asked to care for desperately sick typhoid patients with intestinal perforations and other complications.
Recommendations
1. Typhoid fever should be suspected in young children and infants with fevers of unknown origins in endemic regions.
2. Filtration and chlorination are the two important steps in ensuring a safe water supply. In urban areas safe drinking water should be made available though piped systems or trucked tankers.
3. Appropriate food handling is essential: washing hands with soap before preparing and handling food; eating only cooked or still hot food; avoiding raw food, shellfish, ice.
4. Appropriate systems for human waste disposal must be available for the entire community.
5. Countries with high rates of typhoid fever should consider mass immunization programs using new Vi and Ty21a vaccines for those more than 2 years of age.
6. In hospitals where microbiological facilities are available for the culture of salmonella spp., bone marrow samples, as well as blood and stool should be obtained in patients when typhoid fever is suspected.
7. Testing should include stools of recovering patients at 3 months or urine in regions where schistosomiasis is common, to detect the carrier state.
8. The Widal test cannot be used in the diagnosis without assessing background antibody levels in the population. Better serologic tests should be available soon.
9. Antibiotic therapy should be based on the sensitivity spectrum of local S. typhi strains. Chloramphenicol, ampicillin or co-trimazole may be adequate agents if strains are susceptible.
10. In regions where MDR strains are known to exist, fluroquinolones are the agents of choice.
11. In regions where MDR strains exist and where quinolone use has been extensive, testing for relative flouroquinolone resistance with nalidixic acid discs should be undertaken.
12. Patients, with “severe typhoid” manifested by hypotension and/or altered state of consciousness, should receive short term high dose steroid therapy.
13. The treatment of typhoid perforation is aggressive resuscitation using broad spectrum antibiotics against enteric organisms, prompt surgery with examination of the entire small bowel and right colon with resection (local or segmental) of all full thickness ulcers and perforations.
Brian Ostrow MD, FRCS(C)
Guelph, Ontario, Canada
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Reference List
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Ref Type: Pamphlet
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