Typhoid Fever (Infection Caused by Salmonella Typhi) in Adults: Clinical Guidelines

List of Abbreviations

WHO - World Health Organization

CDC — Centers for Disease Control and Prevention

CHI — Compulsory Health Insurance

ICD-10 — International Statistical Classification of Diseases and Related Health Problems 10th Revision

PMS — Simple Medical Service

Russian Ministry of Health - Ministry of Health of the Russian Federation

OKONH - All-Russian Classifier of Branches of the National Economy

Federal Law

*(3) - international nonproprietary name or chemical name of the medicinal product, or in their absence, the trade name of the medicinal product

*3* - included in the list of vital and essential drugs for medical use

*3** - list of medicinal products for medical use, including medicinal products for medical use prescribed by decision of medical commissions of medical organizations

*3*** - minimum assortment of medicinal products required for the provision of medical care

PTI - Food-borne toxicoinfection

ITSH - Infectious-toxic shock

KIZ - Infectious diseases outpatient clinic

US — Ultrasound

IFA - Enzyme-linked immunosorbent assay (ELISA)

RT-PCR - Real-time polymerase chain reaction

RCoA - Coagglutination test

RIF - Immunofluorescence assay

AMP - Antimicrobial agents (systemic antibacterial drugs)

LPU - Medical and prophylactic institution

MIC - Minimum inhibitory concentration

MR - Methodological recommendations

MU - Methodological guidelines

OKZ - Acute intestinal disease

RPGA - Passive hemagglutination test

SP - Sanitary and epidemiological rules

Ig M - Immunoglobulin M

Ig G - Immunoglobulin G

MDR - Multidrug resistance

MPS - Mononuclear phagocyte system

Terms and Definitions

Evidence-based medicine is an approach to medical practice where decisions regarding the use of preventive, diagnostic, and therapeutic measures are made based on available evidence of their efficacy and safety, and such evidence is sought, compared, synthesized, and widely disseminated for use in the best interest of patients.

Disease – a disorder of bodily function, working capacity, and the ability to adapt to changing environmental and internal conditions arising from the impact of pathogenic factors, accompanied by alterations in the body's protective-compensatory and protective-adaptive reactions and mechanisms.

Quality of medical care – a set of characteristics reflecting the timeliness of medical care, the correctness of the choice of prevention, diagnosis, treatment, and rehabilitation methods during the provision of care, and the degree of achievement of the planned result.

Clinical guidelines – a document based on proven clinical experience that describes the physician's actions regarding the diagnosis, treatment, rehabilitation, and prevention of diseases, helping them make correct clinical decisions.

Level of certainty of evidence – reflects the degree of confidence that the found effect of a medical intervention is true.

Level of recommendation certainty – reflects not only the degree of confidence in the validity of the intervention's effect, but also the degree of confidence that following the recommendations will bring more benefit than harm in a specific situation.

Instrumental diagnostics – diagnostics using various devices, apparatuses, and instruments to examine a patient.

Laboratory diagnostics – a set of methods aimed at analyzing test material using various specialized equipment.

Medical intervention – diagnostic and/or therapeutic medical examinations and/or procedures, as well as artificial termination of pregnancy, performed by a medical professional or other employee authorized to carry out medical activities, affecting the physical or mental state of a person and having a preventive, diagnostic, therapeutic, rehabilitative, or research focus.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Typhoid fever (typhus abdominalis) is an acute anthroponotic infectious disease caused by S. enterica serotype Typhi, characterized by fever, symptoms of general intoxication, bacteremia, ulceration of the lymphatic apparatus predominantly of the small intestine, and hepatosplenomegaly [1, 2, 3, 4, 5, 11, 12, 18].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The causative agent belongs to the family Enterobacteriaceae, genus Salmonella, species enterica, subspecies I (enterica). The full name of the causative agent is Salmonella enterica serotype Typhi. In routine practice, abbreviated names may be used: Salmonella ser. Typhi or Salmonella Typhi, or S. Typhi; [1, 2, 3, 4, 5, 12, 18].

Biological properties of the causative agent: The population of Salmonella enterica serotype Typhi strains comprises motile, non-spore-forming gram-negative rods. They are facultative anaerobes and grow well on ordinary nutrient media. They ferment xylose and arabinose variably, and based on this characteristic, four fermentative variants of S. Typhi (I-IV) are distinguished, which serve as epidemiological markers of the strains [1, 2, 3, 4, 5, 12, 18]. Upon its destruction, endotoxin is released. The antigenic structure of S. Typhi is represented by O-, H-, and Vi-antigens, which determine the production of corresponding agglutinins. S. Typhi preserves relatively well at low temperatures and is sensitive to heat: it dies within 45–60 min at 56 °C, after 30 min at 60 °C, and within a few seconds upon boiling (almost instantaneously at 100 °C). A favorable medium for the bacteria includes food products (milk, sour cream, cottage cheese, minced meat, aspic), in which they not only survive but are also capable of multiplication [1, 2, 3, 4, 5, 12, 18].

Once inside the human body, bacteria penetrate cells and, under the influence of cellular enzymes and other factors, transform into L-forms. L-forms of S. Typhi persist predominantly in bone marrow cells and the reticuloendothelium. The immunogenicity of L-forms is sharply reduced, which contributes to their lifelong persistence in the body and the development of the carrier state [1, 2, 3, 4, 5, 12, 18].

Features of the infectious process in typhoid fever include pronounced lymphotropism of S. Typhi, a hyperergic nature of inflammation in intestinal foci of infection, and high toxicity of the endotoxin.

S. Typhi is a relatively "young" pathogen characterized by high genome conservation and pronounced population clonality. The global population of the typhoid fever pathogen, including S. Typhi strains imported into the territory of the Russian Federation, is represented by strains resistant to antibacterial drugs derived from quinolones — this is a prognostic sign of clinical ineffectiveness of typhoid therapy with fluoroquinolones. Pathogens with a low level of resistance to fluoroquinolones have spread globally over the past 15 years in various regions of Asia: Tajikistan, Uzbekistan, Vietnam, India, Pakistan, Bangladesh, as well as in industrially developed countries such as the USA and Great Britain, where most cases of typhoid fever are associated with visiting "endemic countries of Asia". More than 80% of S. Typhi strains isolated in 2005–2020 were characterized as resistant to quinolone-derived antibacterial drugs and fluoroquinolones [47, 48, 49]. The level of resistance to quinolone-derived antibacterial drugs depends on the number of mutations of the oligonucleotide substitution type in the chromosomal genes gyrA and parC, which encode the target of action of quinolones (quinolone-derived antibacterial drugs), namely topoisomerases. Strains with a single substitution (mutation) exhibit low-level resistance. Strains with multiple mutations exhibit high-level resistance. Overall, only 9.4% of strains were susceptible to systemic antibacterial drugs; 87.6% were resistant to quinolone-derived antibacterial drugs; a multidrug-resistant (MDR) phenotype was noted in 3.0% of strains (quinolone-derived antibacterial drugs, ampicillin**, chloramphenicol**, co-trimoxazole [sulfamethoxazole + trimethoprim]**, tetracycline).

Assessment of the phylogenetic proximity of S. Typhi strains imported into the Russian Federation in 2005–2020 showed that 80% of Russian strains belonged to a "successful international Asian clone" belonging to a single genetic group, the "H58 haplotype (genotype)," and most likely originated from South and Southeast Asian countries. Such strains caused typhoid fever cases in various territories of the Russian Federation over different years [47, 48, 49].

The pathogenesis of typhoid fever is characterized by cyclicity and the development of specific pathophysiological and morphological changes. Infection occurs via the oral route, with the digestive tract serving as the primary site of localization of the pathogens. It should be specifically noted that infection does not always lead to the development of the disease. The pathogen may perish in the stomach under the influence of the bactericidal properties of gastric juice or even within the lymphoid formations of the small intestine. Having overcome the gastric barrier, the pathogen enters the small intestine, where it multiplies and becomes fixed by solitary and aggregated lymphoid follicles with subsequent accumulation of the pathogen, which spreads via lymphatic vessels to the mesenteric lymph nodes. These processes are accompanied by inflammation of the lymphoid elements of the small intestine, and frequently the proximal large intestine, as well as lymphangitis and mesadenitis. They develop during the incubation period, at the end of which the pathogen breaks into the bloodstream and bacteremia develops, increasing in intensity day by day. Under the influence of the bactericidal systems of the blood, the pathogen is lysed, lipopolysaccharides (LPS) are released, and intoxication syndrome develops, manifested by fever, central nervous system involvement in the form of adynamia, lethargy, sleep disorders, and autonomic nervous system dysfunction characterized by skin pallor, decreased heart rate, intestinal paresis, and delayed stool. This period roughly corresponds to the first 5–7 days of the disease. Inflammation of the intestinal lymphoid elements reaches its maximum and is characterized as medullary swelling. Bacteremia is accompanied by dissemination to internal organs, primarily the liver, spleen, kidneys, and bone marrow, where specific inflammatory granulomas form. This process is accompanied by increasing intoxication and the appearance of new symptoms: hepatosplenomegaly, aggravated neurotoxicosis, and characteristic changes in the hemogram. Concurrently, phagocytosis is stimulated, bactericidal antibodies are synthesized, specific body sensitization occurs, and the excretion of the pathogen into the environment via bile and the urinary system increases sharply. Sensitization manifests as the appearance of a rash, the elements of which represent a focus of hyperergic inflammation at the site of pathogen accumulation in the cutaneous vessels. Re-penetration of the pathogen into the intestine causes a local anaphylactic reaction in the form of necrosis of lymphoid formations. In the third week, there is a trend toward a decrease in the intensity of bacteremia. Organ lesions persist. In the intestine, necrotic masses are sloughed off and ulcers form, the presence of which is associated with typical complications of typhoid fever — ulcer perforation with the development of peritonitis and intestinal hemorrhage. It should be emphasized that hemostatic disorders play a significant role in the development of bleeding. In the 4th week, the intensity of bacteremia drops sharply, phagocytosis is activated, granulomas in organs regress, intoxication subsides, and body temperature decreases. Intestinal ulcers cleanse and begin to scar, and the acute phase of the disease concludes. However, due to imperfect phagocytosis, the pathogen may persist within cells of the mononuclear phagocyte system, which, in the event of insufficient immunity, leads to exacerbations and relapses of the disease, and in the presence of immunological insufficiency, to chronic carriage, which in typhoid fever is considered a form of the infectious process. In this case, the pathogen spreads from the primary foci within the mononuclear phagocyte system into the blood and subsequently into the bile and urinary system, forming secondary foci. In such instances, chronic cholecystitis and pyelitis are possible. Immunity following typhoid fever is long-lasting, though recurrent cases can occur 20–30 years later. Due to the use of antibiotic therapy and insufficient persistence of immunity, recurrent cases of the disease occur earlier [1, 2, 3, 4, 5, 12, 18].

1.3 Epidemiology of the Disease or Condition

The Russian Federation is not among the countries endemic for typhoid fever. Over recent decades, the epidemiological situation has been assessed as stable against the background of a steady downward trend in morbidity.

In 2005–2020, cases were registered in 63 constituent entities, mostly as sporadic single cases. The importation of typhoid fever from endemic territories by foreign tourists, students studying at Russian universities, migrant workers, and Russian citizens vacationing in endemic countries (most frequently Central, South, and Southeast Asia) is noted annually. According to summary data for 2005–2020, the "importation" of typhoid fever was established from 13 countries: Abkhazia, Azerbaijan, Bangladesh, Egypt, India, Cambodia, Kyrgyzstan, Madagascar, Nepal, United Arab Emirates, Pakistan, Tajikistan, Uzbekistan [47, 48, 49].

In 2017–2020, 40 cases of typhoid fever were registered in the Russian Federation across six Federal Districts: Central — 20 cases (2017–2019); North-Western — 8 cases (annually in 2017–2020); Southern — 1 case (2019); Volga — 2 cases (2017 and 2019); Ural — 3 cases (2017–2018); Siberian — 6 cases (2017–2018). Typhoid fever was not registered in two Federal Districts (North Caucasian and Far Eastern) in 2017–2020. The absolute number of cases was: 24 in 2017; 9 in 2018; 6 in 2019; 1 in 2020 [47, 48, 49].

Of the 40 registered cases of typhoid fever, 38 patients were adults, of whom 37 lived in urban areas and 1 in rural areas. Two cases were registered in school-age children (aged 7 to 14 years) in 2017 [47, 48, 49].

Underestimation of epidemiological and clinical data at the pre-hospital stage persists, which requires increased attention to patients who visited countries with warm and hot climates endemic for typhoid fever within the incubation period, as well as to homeless individuals and patients with long-term fever accompanied by diarrheal syndrome [47, 48, 49].

For over 10 years, no autochthonous cases of typhoid fever have been registered in the territories served by the FMBA of Russia [55].

The source of infection in typhoid fever is a human: a bacteria carrier or a typhoid fever patient; the predominant transmission mechanism is fecal-oral, realized through foodborne, waterborne, and contact-household transmission routes of the pathogen. A modern feature of typhoid fever epidemiology is a sharp increase in the frequency of infection importation from territories endemic for typhoid fever in Southeast Asian countries [1, 2, 3, 4, 5, 12, 13, 18].

Given the global intensive labor migration and the growth of international tourism observed in recent years, including to countries with a high incidence of typhoid fever, the "importation" of infection into the Russian Federation and the development of group outbreaks of typhoid fever can occur at any moment.

Over the past 10 years, the "importation" of typhoid fever by migrant workers and tourists into Russia from 13 countries has been noted¹.

Susceptibility to typhoid fever is significant. The contagiousness index is 0.4. Individuals aged 15 to 40 years are most commonly affected. A sustained, usually lifelong immunity develops after the disease; however, in recent years, due to antibiotic therapy in patients and its immunosuppressive effect, the intensity and duration of acquired immunity appear to have decreased, resulting in an increased frequency of reinfection with typhoid fever [1, 2, 3, 4, 5, 12, 13, 18].

¹SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" XXVII. Prevention of typhoid fever and paratyphoid fevers (Registered with the Ministry of Justice of Russia on 15.02.2021, No. 62500).

1.4 Features of Coding the Disease or Condition

A01.0 – Typhoid fever

1.5 Classification of the disease or condition

By clinical forms:

1. manifest forms;

2. submanifest (asymptomatic) forms.

By clinical form:

Typical

Atypical:

2.1. Mild / aborted;

2.2. Aborted.

Rare forms (pneumotyphoid, meningotyphoid, nephrotyphoid, colotyphoid, appendicotyphoid, cholangiotyphoid, typhoid gastroenteritis).

By severity:

Mild

Moderate

Severe

By duration of the course:

Cyclic

Relapsing

By the presence of complications:

Uncomplicated

Complicated:

– specific complications (intestinal hemorrhage, intestinal perforation).

The main criteria for assessing the severity of typhoid fever are hemodynamic parameters (pulse, blood pressure), duration of fever at the peak of the disease, and complications. The severity is determined by at least three clinical parameters – Appendix A3.

When complications develop, the severity is assessed as severe regardless of other clinical parameters.

1.6 Clinical presentation of the disease or condition

Typhoid fever (typical form)

The incubation period ranges from 3 to 21 days (most commonly 9 to 14 days, rarely up to 60 days) and depends on the infecting dose and the condition of the macroorganism.

The following periods of the disease are distinguished:

• Initial

• Peak period of the disease

• Fading of clinical manifestations (resolution)

• Convalescence

In the classical course, many complications (both specific and nonspecific) were previously observed, which determined the outcome of the disease.

The onset of typhoid fever is gradual or acute (in more than 50% of patients). Typhoid fever may begin in the manner of gastroenteritis, a pseudomalarial paroxysm, meningitis, biliary tract disease, respiratory syndrome, or upper respiratory tract catarrh.

With a gradual onset, body temperature and general intoxication increase slowly, accompanied by malaise, weakness, fatigue, chills, decreased appetite up to anorexia, headache, sleep disturbance, and myalgia. In other cases, there is a rise in body temperature up to 38–39⁰°C for a duration of 4–7  days. The fever is of a continuous type, lasting up to 4–5 weeks (body temperature is initially low, then progressively rises, reaching by the beginning of the second week 38-39⁰°C, and becomes continuous (indicating pronounced toxinemia). Nausea, abdominal discomfort without clear localization (flatulence and abdominal distension), constipation, or diarrhea with characteristic "pea soup" stool are observed. By the end of the 1st week of the disease, the headache reaches its maximum severity. The patient's appearance is characteristic: adynamia, pallor of the skin; The skin is hot and dry. Angina may be observed. The tongue is thickened, coated with a white plaque, with teeth indentations along the edges ("typhoid tongue"). The abdomen is moderately distended, with gurgling and shortening of the percussion sound in the right iliac fossa (Padalka's sign). Sometimes pronounced abdominal pain mimicking appendicitis is observed. Regarding the cardiovascular system, relative bradycardia may be noted in the initial period.

With an acute onset of the disease, the initial period is shortened, the temperature rises to high levels within 2 days, accompanied by chills and rapidly increasing general intoxication, reaching maximum severity by the 5th–7th day of the disease. The temperature remains high, is resistant to specific etiotropic therapy, and most often has a wave-like character. Infectious-toxic encephalopathy ("typhoid state") develops in 20–46% of patients, whereas other patients exhibit its equivalents in the form of headache, sleep disturbances, and adynamia. The skin of the palms and soles is yellowish (Philippovich's sign). From the 8th–9th day of the disease, roseolous exanthema (roseola elevata) appears on the skin. The rash is usually scanty; profuse rashes are more common in severe forms of the disease. Isolated roseolae are most frequently located on the skin of the lower chest, back, and abdomen, and very rarely on the extremities. In the first days of appearance, roseolae are pale and juicy, with fairly distinct contours; in subsequent days, they are flat but bright. The duration of roseola persistence is 2–4 days (they disappear completely or leave pigmentation for a long time). Successive appearance of new roseolae is characteristic. Eruptions may be observed throughout the entire febrile period of the disease and sometimes even during normal temperature. In severe forms, the rash may be hemorrhagic, which is an unfavorable prognostic sign. The rash is a key diagnostic sign in typhoid fever, occurring in 50–60% of patients.

During the peak of the disease, the tongue becomes dry, coated with a gray or brownish plaque, sometimes a thick dirty-brown plaque (fuliginous tongue). There is meteorism, as well as gurgling in the right iliac region. Stool is usually absent, but in some cases can be loose up to 4–5 times a day, resembling pea soup. The liver and spleen are clearly enlarged, of medium density. Hypotension is noted, heart sounds are muffled, and along with relative bradycardia, many patients exhibit pulse dicrotism. Changes in the respiratory system are characterized by phenomena of bronchitis or pneumonia.

Towards the end of the 2nd week of the disease, the phase of maximum development of the disease sets in, lasting about 2 weeks. Marked intoxication, clouded consciousness, delirium, hand tremor, convulsive twitching of facial muscles, involuntary urination and defecation, decreased blood pressure are noted; relative pulse bradycardia and muffled heart sounds persist.

Complete blood count in the first 2–3 days of the disease is characterized by moderate leukocytosis, replaced by leukopenia with a left shift of the formula, an- or eosinophilopenia, and relative lymphocytosis. Hemoglobin content and platelet count may be reduced. ESR is moderately accelerated. Leukocytosis in the first days often goes undetected. Liver enzyme levels exceed the upper limit of norm by 2–3 times.

During this period of the disease, complications may develop: nasal and intestinal hemorrhages, perforation of small intestine ulcers, in addition to pneumonia, otitis, myocarditis, pyelitis, meningitis, infectious psychosis, etc.

In mild and moderate courses, central nervous system and cardiovascular disorders are moderately expressed.

At the peak of the disease, urine output decreases. Proteinuria, microhematuria, and cylindruria are detected. Bacteriuria occurs, which can lead to inflammation of the renal pelves and urinary bladder mucosa.

Possible complications: orchitis, epididymitis, dysmenorrhea, premature birth or miscarriages in pregnant women, as well as intestinal hemorrhage and perforation of typhoid ulcers.

In the fading phase of clinical symptoms, temperature gradually decreases, most often by short lysis, and then normalizes. Well-being improves, appetite appears, lethargy, headache, meteorism disappear, the tongue clears, liver and spleen sizes decrease, and diuresis increases.

The convalescence period begins with the normalization of temperature and the restoration of impaired bodily functions. Its duration is 2–3 weeks depending on the severity of the disease. Asthenia, irritability, and vegetative-vascular dystonia may persist for a long time. During this time, complications such as myocarditis, thrombophlebitis, osteomyelitis, cholecystitis, etc., are observed.

The convalescence period lasts for 2–3 weeks; subfebrile temperature is possible as a result of vegetative-endocrine disorders. In 3–5% of cases (up to 12% and higher according to some data), chronic bacteriocarrier state develops.

However, before temperature normalization, exacerbations are possible, which are characterized by increasing fever and intoxication, the appearance of fresh roseolae, and enlargement of the spleen. Exacerbations are observed more often with improper treatment, including the use of a systemic antibacterial drug to which the pathogen is resistant.

The severity of the disease is assessed by the degree of intoxication, the height and duration of fever, and the nature and number of complications [1, 2, 3, 4, 5, 12, 13, 18].

Features of the modern course of typhoid fever

Changes in the clinical picture are associated with the frequent use of systemic antibacterial drugs and vaccines for the prevention of typhoid fever. Mild forms have become more frequent, in which general intoxication phenomena are weakly expressed, and many symptoms of the classical course are absent. Fever lasts 5–7 days (sometimes 2–3 days) even without the use of antibacterial drugs.

In 60–80% of cases, the onset of typhoid fever is acute, and lymphadenopathy is detected. Atypically proceeding cases present diagnostic difficulties, for example, typhoid fever with the clinical picture of acute gastroenteritis and short-term fever (1–3 days).

During the reconvalescence period against the background of normal body temperature, complications can develop in the form of intestinal ulcer perforation (sometimes patients are admitted to the surgical department of a non-infectious hospital!).

Laboratory test results have also undergone changes. In almost half of the patients, normocytosis is observed, and eosinophils persist in the blood. Serological reactions may remain negative throughout the entire disease [1, 2, 3, 4, 5, 12, 13, 18, 31, 32].

Features of the course of typhoid fever in hot climates

The disease proceeds in hot climates against the background of water-electrolyte balance disorders, decreased general reactivity, immunodeficient state, often in combination with other infections common in the given area (malaria, viral hepatitis, amebiasis, dysentery, etc.).

A more acute onset of the disease is characteristic. The increase in body temperature is generally accompanied by chills, often recurrent. The fever rapidly, within 1–2 days, reaches its maximum.

From the very beginning, patients complain of severe general weakness, headache predominantly in the frontal region, dry mouth, intense thirst, myalgia and arthralgia in the lower extremities, and bowel dysfunction. Stools occur up to 3–4 times daily, are loose/liquid, light brown or greenish in color, without pathological impurities.

Symptoms of rhinitis and pharyngitis frequently develop (rhinorrhea with scarce serous discharge, scratchy throat, moderate hyperemia of the oropharyngeal and nasal mucous membranes).

During the first days of illness, the patient's face may be flushed, later turning pale. The pulse is initially rapid, becoming typical (relative bradycardia) only at the height of the disease. The tongue is rapidly coated with a dryish brownish fur. Without timely prophylactic measures, bleeding fissures develop on it. In the first days of illness, abdominal palpation reveals rumbling and splashing sounds along the large and small intestines [1, 2, 3, 4, 5, 12, 13, 18].

Relapsing typhoid fever is recorded in 10–15% of patients. A relapse is defined as the recurrence of clinical typhoid symptoms following an afebrile period lasting at least 2 weeks.

Widespread use of systemic antibacterial drugs leads to later relapses in typhoid fever patients (often after 1 month or more of apyrexia). In patients who did not receive etiotropic therapy, relapses develop earlier—starting from day 14 of apyrexia. Early discontinuation of systemic antibacterial drugs results in relapses in 20–30% of patients.

Harbingers of relapse include persistent low-grade fever after temperature normalization, tachycardia, hepatosplenomegaly, adynamia, persistent aneosinophilia, positive cultures, and low antibody titers.

Clinically, a relapse runs a milder course with a shorter febrile period. The number of relapses can range from 1 to 5 or more [1, 2, 3, 4, 5, 12, 13, 18].

Atypical typhoid fever

The abortive form is characterized by a typical onset, but with a rapid (within 5–7, sometimes 2–3 days), often critical drop in temperature, resolution of all symptoms, and transition into convalescence.

The subclinical/mild form ("typhus levissimus", ambulatory typhoid) is characterized by transient low-grade fever, mild signs of intoxication, and the absence of many typical features of the disease (bradycardia, meteorism, rash). Body temperature throughout the illness does not exceed 38⁰C, and intoxication is minimal.

Rare forms (pneumotyphoid, meningotyphoid, encephalotyphoid, colotyphoid, appendicotyphoid, cholangiotyphoid, nephrotyphoid). The clinical presentation is dominated by symptoms characteristic of damage to a particular organ. At the same time, core signs of a generalized process persist (hepatosplenomegaly, small intestine involvement, etc.).

Bacteriologic carriage

A proportion of recovered individuals may become bacterial carriers and lifelong sources of the pathogen, presenting a high epidemiological risk.

Typhoid fever can lead to acute and chronic carrier states, which are categorized as follows:

- Acute carriers: individuals recovering from typhoid fever in whom clinical recovery precedes microbiological clearance of the pathogen, which may be shed in the urine and feces for up to 3 months post-infection;

- Chronic carriers: individuals who shed the pathogen for more than 3 months post-infection, including throughout their entire life. They represent at least 3–5% of recovered patients. Shedding by chronic carriers may be intermittent (the pathogen is not shed continuously), which complicates their detection;

- Transient carriers: individuals with a single isolation of the pathogen on stool culture in the absence of clinical manifestations or a history of the disease. The presence of bacteria in bile or urine samples excludes a transient carrier status. Such carriage can occur when typhoid pathogens enter the intestines of an immune host (vaccinated against typhoid fever) or following exposure to a low, subinfectious dose of the pathogen.

Determination of the carriage type and differentiation of chronic carriage from transient and subclinical forms of the disease are performed in healthcare facilities¹ [1, 2, 3, 4, 5, 12, 13, 18].

Complications

Intestinal hemorrhage most often occurs at the end of the second and during the third week of illness. It may be profuse or mild, depending on the caliber of the ulcerated blood vessel, coagulation status, thrombus formation, blood pressure, etc. In some cases, it presents as capillary bleeding from intestinal ulcers. Some authors note that transient blood pressure elevation, loss of pulse dicrotism, tachycardia, a critical temperature drop, and diarrhea should raise concern for intestinal hemorrhage. Flatulence and hyperperistalsis promote bleeding. The direct sign of bleeding is melena (tarry stools). Fresh red blood is sometimes present in the stool. General signs of internal bleeding include pallor, a drop in blood pressure, tachycardia, and a critical drop in body temperature, accompanied by clearing of consciousness and increased patient alertness, creating a false impression of clinical improvement. Massive hemorrhage can precipitate hemorrhagic shock, carrying a grave prognosis. Due to reduced circulating blood volume caused by blood pooling in the splanchnic vessels, patients are highly sensitive to blood loss, and systemic signs of hemorrhage may appear with blood losses significantly smaller than in healthy individuals. Hemorrhages from the large intestine are the most dangerous. Bleeding can be single or recurrent—up to 6 times or more—and may last for several hours due to coagulation disorders [1, 2, 3, 4, 5, 12, 13, 18].

A more ominous complication is intestinal perforation, observed in 0.5–8% of patients. Observations indicate that there is no correlation between anatomical lesions and the severity of intoxication, making perforation difficult to predict. It occurs most often in the terminal ileum, approximately 20–40 cm from the ileocecal valve. Usually, a single perforation (rarely two, three, or more) up to 1.5 cm in size develops. Rarely, perforation occurs in the colon, gallbladder, or appendix, the lymphoid apparatus of which is actively involved in the inflammatory process. Perforations are usually single, though triple and quintuple perforations occur, and they are more frequent in men. Clinical manifestations of perforation include acute abdominal pain localized to the umbilical region slightly to the right of the midline, abdominal guarding, and a positive Blumberg's sign. The pulse is rapid and weak, the face turns pale, the skin is covered with cold sweat, breathing is accelerated, and severe collapse is noted in some cases. The most critical clinical signs of intestinal perforation are pain, muscular guarding, meteorism, and absent peristalsis. Pain, particularly "knife-like" pain, is not always pronounced, especially in the presence of the typhoid state (status typhosus), which often leads to diagnostic errors. Important signs include meteorism combined with hiccups, vomiting, dysuria, and loss of hepatic dullness. Regardless of pain intensity, localized muscular rigidity in the right iliac fossa is detected, but as the process advances, abdominal rigidity becomes more diffuse and pronounced. Intestinal perforation is promoted by flatulence, hyperperistalsis, and abdominal trauma. Peritonitis can also develop from deep penetration of typhoid ulcers, necrosis of mesenteric lymph nodes, suppuration of a splenic infarct, or typhoid salpingitis. Late hospitalization and delayed specific therapy predispose to intestinal hemorrhage and perforation. The presentation of perforation and peritonitis on antibiotic therapy is often masked; therefore, even mild abdominal pain should alert the physician, while worsening fever, intoxication, meteorism, tachycardia, and leukocytosis, even without localized signs, point to the development of peritonitis [1, 2, 3, 4, 5, 12, 13, 18].

In 0.5–0.7% of patients, typically at the peak of the illness, septic/toxic shock develops. The clinical presentation of septic shock is characterized by sudden acute deterioration, chills, hyperthermia, confusion, arterial hypotension, leukopenia, and neutropenia. The skin becomes pale, moist, and cold, cyanosis and tachycardia progress, and respiratory failure ("shock lung"/ARDS) and oliguria develop. Azotemia (elevated urea and creatinine concentrations) is detected on blood tests [1, 2, 3, 4, 5, 12, 13, 18].

Prognosis

In the pre-antibiotic era, the mortality rate for typhoid fever was 3–20%, whereas with modern therapy it is 0.1–0.3% [1, 2, 3, 4, 5, 12, 13, 18].

¹SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" XXVII. Prevention of typhoid fever and paratyphoid fevers (Registered with the Russian Ministry of Justice on February 15, 2021, No. 62500).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for Establishing the Diagnosis/Condition

The diagnosis of typhoid fever is based on pathognomonic findings [1, 2, 3, 4, 5, 6, 11, 12, 26, 27]:

1) anamnesis data: consumption of infected (or potentially infected) food or water 8–72 hours prior to the onset of the disease, contact with a typhoid fever patient; contact with chronic bacterial carriers, convalescents, or visitors from typhoid-endemic areas; presence in an endemic focus or contact with a prolonged febrile patient of unclear etiology; staying in an area unfavorable for typhoid fever for 3–6 weeks before the onset of the disease;

2) complaints and physical examination findings: cyclicity of the disease, gradual or acute (in more than 50% of patients) onset, gradual or rapid increase in body temperature, prominent intoxication symptoms (headaches, sleep inversion, weakness, lethargy, adynamia, dry mouth, thirst, loss of appetite), lymphadenopathy, roseolous rash, constipation or diarrheal syndrome with characteristic stool ("pea soup"), vagotonia phenomena (pallor of the skin, abdominal distension, relative bradycardia, muffled heart sounds, decreased blood pressure, fuliginous tongue), appearance of encephalopathy due to infection and toxemia ("typhoid state") at the peak of the disease, hepatosplenomegaly, and pathognomonic Padalka's and Filipovich's signs;

3) laboratory tests: isolation of S. typhi from clinical material;

4) instrumental examination data are not used for routine diagnostics.

2.1 Complaints and Anamnesis

Typhoid fever is characterized by disease cyclicity, gradual or acute (in more than 50% of patients) onset, gradual or rapid elevation of body temperature, pronounced symptoms of intoxication (headaches, sleep inversion, weakness, lethargy, adynamia, dry mouth, thirst, loss of appetite), lymphadenopathy, roseolous rash, constipation or diarrhea with characteristic stool ("pea soup"), signs of vagotonia (pale skin, abdominal distension, relative bradycardia, muffled heart sounds, decreased blood pressure, fuliginous tongue), development of infectious-toxic encephalopathy ("typhoid status") at the peak of the disease, hepatosplenomegaly, and pathognomonic Padalka's and Filipovich's signs. Chronic bacterial carriage develops in 3–5%, and according to some sources up to 12% or more, of cases [1, 2, 3, 4, 5, 11, 12].

- whether there was contact with a patient with typhoid fever; contact with chronic bacterial carriers, convalescents, or visitors from typhoid-endemic areas; visiting endemic areas;

- staying in an outbreak or contact with a patient with prolonged fever of unknown origin; staying in an area unfavorable for typhoid fever for 3–6 weeks before the onset of the disease;

- consumption of water (from open water bodies, tap water, bottled water, etc.), vegetables, fruits, food products and ready-to-eat meals (salads, vinaigrettes, cold meat dishes), liquid and semi-liquid food products, soft drinks, etc., potentially secondarily contaminated, not meeting hygienic standards, or purchased in unauthorized trading places;

- non-compliance with personal hygiene rules.

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: infection can occur as a result of drinking contaminated water; consuming contaminated meat and dairy products; via contaminated hands and household items, especially in 24-hour patient care facilities (hospitals, psychoneurological residential facilities).

2.2 Physical Examination

Comments: in severe cases of typhoid fever, patients may develop infectious-toxic shock during the 2nd–3rd week of the disease.

Comments: during the 2nd–3rd week of typhoid fever, necrotic masses are sloughed off in the intestine, followed by the formation of ulcers, which in some cases can lead to intestinal perforation and hemorrhage [25, 26].

Comments: in the 3rd week of the disease, less frequently at earlier times (11th–13th day of the disease), intestinal perforation may occur. Perforation most frequently occurs in the ileocecal region, more often in the terminal ileum, 20–30 cm from the ileocecal valve, as a single or, less frequently, two perforation holes [25, 26].

2.3 Laboratory Diagnostics

At the diagnostic stage:

Comments: clinical and biochemical blood parameters vary depending on the period of the disease. The complete (clinical) blood count in the first 2–3 days of the disease is characterized by moderate leukocytosis, which is replaced by leukopenia with a left shift in the leukocyte formula, an- or eosinophilopenia, and relative lymphocytosis. Hemoglobin levels and platelet counts may be reduced, with an accelerated ESR. At the peak of the disease, proteinuria, microhematuria, cylindruria, and bacteriuria are detected in the general (clinical) urinalysis. In cases of chronic S. typhi shedding, the complete blood count reveals moderate lymphocytosis and normocytosis, and occasionally leukocytosis and accelerated ESR. In recent years, the diagnostic value of hematological shifts in typhoid fever patients has been decreasing [1, 2, 3, 4, 5, 6, 11, 12, 26, 27].

Comments: the general biochemical blood test shows elevated levels of amylase and urea, moderate hyperenzymemia (2–3 fold) (ALT, AST), total bilirubin within normal limits or slightly increased; hypokalemia, hyponatremia, hypocalcemia.

Comments: molecular biological study of feces / rectal swab is carried out using nucleic acid amplification methods (NAAM), including real-time PCR, reverse transcription PCR, isothermal amplification methods, and others, using multiplex diagnostic systems for the presence of viral and bacterial pathogens of acute intestinal infections. Materials for bacteriological study for the diagnosis of typhoid fever include blood (from the 1st day of the disease, throughout the entire febrile period, and in case of relapse, even at normal body temperature); stool and urine throughout the entire period of the disease. Examination of autopsy material is performed to clarify the diagnosis [1, 2, 3, 4, 5, 6, 11, 12, 26, 27, 46].

Comments: serodiagnosis of typhoid fever allows the detection of specific IgG antibodies to O-antigens of S. typhi [1, 9, 12] and Vi-antigen. Clear, non-hemolyzed blood serum is used for serological studies (MU 4.2.2039-05). The study is performed dynamically with an interval of 7–10 days. Not only the presence of a "diagnostic" titer (1:160 in non-endemic areas and 1:640 in endemic regions and higher) is important, but a fourfold or greater change in the antibody titer in paired sera, starting from the 7th day of the disease (onset of agglutinin production).

This diagnostic method allows confirming the diagnosis in 80–92% of patients, including those with mild and abortive forms of typhoid fever.

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

2.4 Instrumental Diagnostics

Comment: hepatosplenomegaly without changes in liver structure is characteristic of typhoid fever.

Comment: the development of diffuse bronchitis is characteristic of typhoid fever.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Treatment of patients with typhoid fever should be comprehensive and conducted in several directions:

• regimen of strict bed rest;

• thorough hygienic care by medical personnel for patients in severe condition;

• medical nutrition (diet therapy);

• targeting the pathogen;

• detoxification and restoration of homeostasis;

• monitoring of water and electrolyte balance (if necessary);

• elimination of structural and functional gastrointestinal changes;

• restoration of normal intestinal microflora.

3.1. Conservative management

3.1.1 Etiotropic therapy

or #cefixime 400 mg orally (once daily or 200 mg twice daily)) [1, 2, 3, 4, 10, 11, 18, 20, 22, 27, 50-54].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: due to the widespread distribution of S. Typhi strains resistant to chloramphenicol**, ampicillin**, and co-trimoxazole [sulfamethoxazole + trimethoprim]**, fluoroquinolones have become the drugs of choice. Third-generation cephalosporins are an alternative. In mild and moderate typhoid fever, oral formulations of systemic antibacterial drugs can be used, while in severe cases, intravenous administration is preferred.

Comment: the efficacy of the combination of ceftriaxone** intravenously 2 g once daily and #azithromycin** orally 0.5 g once daily for 7 days or 72 hours after normalization of body temperature has been demonstrated [39].

3.1.2 Pathogenetic therapy

Goal of pathogenetic therapy:

- bed rest and diet compliance;

- reduction of intoxication;

- prevention of specific complications (infectious-toxic shock, hemorrhage, intestinal perforation);

- correction of water and electrolyte balance disorders;

- elimination of structural and functional gastrointestinal changes;

- restoration of normal intestinal microflora.

Comments: sudden movements, heavy lifting, and straining during defecation are prohibited for the patient. Rough and deep abdominal palpation by the physician is prohibited, especially during the 2nd–3rd week of the illness! The activity regimen is expanded very cautiously and gradually, under the close monitoring of the patient's general condition and gastrointestinal function parameters (clinical, laboratory, and instrumental).

Comments: organization of therapeutic dietary nutrition for patients with typhoid fever during inpatient treatment in medical organizations is carried out in accordance with orders of the Russian Ministry of Health No. 330 of August 5, 2003, "On measures to improve therapeutic nutrition in healthcare institutions of the Russian Federation," No. 395n of June 21, 2013, "On approval of therapeutic nutrition standards," and No. 1008n of September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition."

• In case of fever in patients, it is recommended to use ibuprofen** orally at 200 mg (1 tablet) up to 3–4 times daily (to achieve a faster therapeutic effect in adults, the dose can be increased to 400 mg (2 tablets) up to 3 times daily) for antipyretic purposes [1, 2, 3, 4, 5, 9, 11, 12].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comment: no more often than every 6 hours; maximum daily dose is 1200 mg for adults.

3.2 Surgical Treatment

3.3 Management tactics for patients with acute and chronic S. Typhi carriage

Treatment of patients with acute and chronic bacterial carriage should be aimed not so much at eradicating the pathogen as at shifting the active, decompensated process into a stage of compensation (latency).

Comments: the choice of treatment agents must take into account comorbidities, susceptibility to systemic antibacterial drugs, drug tolerance, and contraindications.

Comments: treatment of acute and chronic bacterial carriers must be comprehensive and include medications capable of:

1) penetrating inside macrophages at a sufficient concentration and exerting a bactericidal effect on S. Typhi residing within them (macrolides and fluoroquinolones). As a result of treatment, bacterial excretion ceases in a significant number of carriers for various periods (from 2 to 5 years or more), reducing their epidemiological hazard as a source of infection [40, 41, 42];

2) enhancing phagocytic and cellular enzymatic activity;

3) exerting an immunomodulatory effect;

4) enhancing the antioxidant effect.

Comments: the type of drug, dose, and duration of the course are determined individually.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: a gradual increase in graded physical and mental stress is important, as is the differentiated application of various intervention methods.

Comments: the rate and degree of restoration of the functional state and occupationally significant functions of convalescents are taken into account (using indirect and direct methods).

Comments: the medical record includes clinical and etiological diagnoses of the disease, data on the treatment provided, results of the patient's screening for bacterial carriage, and recommendations for follow-up. Upon discharge from the hospital, the sick leave certificate is extended by 10 days; if necessary, the physician at the infectious diseases department (KIZ) may extend it for another 5 days.

Comments: there is a probability of chronic bacterial carriage developing. In addition, the convalescent and individuals in daily contact with them (family members) are additionally informed about the risk of infection, the need for strict adherence to personal hygiene rules, and the procedure for routine disinfection.

Comments: avoid heavy physical labor, jarring rides, hypothermia and overheating, visiting baths and saunas, and sports activities for six months. The consumption of any alcoholic beverages, fatty foods, and spicy foods is strictly prohibited for six months.

5. Prevention and Dispensary Observation

5.1 Prevention1

5.2. Follow-up monitoring1

1. Microbiological (culture) examination of feces for typhoid and paratyphoid pathogens (Salmonella typhi), microbiological (culture) examination of urine for bacterial pathogens using automated seeding at 2-day intervals (10 days after discharge) 5 times;

2. Microbiological (culture) examination of feces for typhoid and paratyphoid pathogens (Salmonella typhi), microbiological (culture) examination of urine for bacterial pathogens using automated seeding monthly for 3 months;

3. Microbiological (culture) examination of feces for typhoid and paratyphoid pathogens (Salmonella typhi), microbiological (culture) examination of urine for bacterial pathogens using automated seeding, and serological blood testing once a year after discharge [1, 2, 3, 4, 5, 6, 17, 18, 29].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: during the observation of this category of patients, various expert issues regarding professional activity, military service, etc., may arise. Therefore, it is advisable to divide the scope of diagnostic and therapeutic care into two stages.

- The first stage is carried out at the outpatient clinic level by an infectious disease specialist or general practitioner in cooperation with a neurologist, nephrologist, and, if necessary, other outpatient subspecialists.

- The second stage is utilized when a specific pathology is identified that requires more detailed clinical, laboratory, and instrumental examination, as well as when expert opinions are needed. At the second stage, physicians and diagnostic services of specialized inpatient departments are involved in the diagnostic and therapeutic process.

¹SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" XXVII. Prevention of typhoid fever and paratyphoid fevers (Registered with the Russian Ministry of Justice on February 15, 2021, No. 62500).

6. Organization of Medical Care

Despite the planning of diagnostic and therapeutic interventions for patients with typhoid fever, the care is of an emergency nature. A delayed start of combination therapy, including etiotropic treatment, leads to a more protracted course of the disease, delayed diagnosis of complications, and may worsen the disease prognosis for a particular patient.

Comments: patient hospitalization is carried out within the first three hours, or within 6 hours in rural areas after receiving the emergency notification.

In areas endemic for typhoid fever, individuals with a fever of unknown origin lasting more than three days are subject to provisional hospitalization, with mandatory blood culture testing. Newly admitted patients are placed separately from convalescents.

• It is recommended to discharge typhoid fever convalescents from the hospital after clinical recovery and three consecutive negative control results of microbiological (culture) examination of feces for typhoid and paratyphoid pathogens (Salmonella typhi), and microbiological (culture) examination of urine for bacterial pathogens using automated inoculation (performed 5 calendar days after the establishment of normal body temperature or 2 calendar days after the end of etiotropic treatment for occupationally exposed groups of patients) [1, 2, 3, 4, 5, 6, 11, 12].

GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).

Comments: the first test is performed 5 days after the normalization of temperature, and subsequent tests at five-day intervals. Convalescents who received systemic antibacterial drugs are discharged from the hospital no earlier than 21 days. Individuals who did not receive systemic antibacterial drugs are discharged no earlier than 14 days after the onset of apyrexia. The detection of S. Typhi during control laboratory testing (prior to hospital discharge) in a patient not belonging to the category of workers of certain professions, industries, and organizations who has no signs of disease is not a contraindication for hospital discharge.

The detection of S. Typhi during control laboratory testing in the absence of disease signs in a patient belonging to the category of workers of certain professions, industries, and organizations is the basis for a repeated course of treatment. In case of continued S. Typhi shedding, such a patient is subject to discharge from the hospital with subsequent dispensary registration indicating S. Typhi carriage and is suspended from work.

Convalescents who do not belong to the "decreed group" and in whom control laboratory testing detects S. typhi excretion are kept in the hospital and receive an additional course of treatment. If the pathogen continues to be detected 1.5–3 months after clinical recovery, the convalescent is discharged home with a diagnosis of S. typhi carriage and is not suspended from work.

Medical care for patients with typhoid and paratyphoid diseases is provided in the form of: - primary health care;

- emergency medical care, including specialized emergency medical care;

- specialized medical care, including high-tech medical care.

Medical care for patients with typhoid and paratyphoid diseases can be provided under the following conditions:

• outpatient (in settings not providing round-the-clock medical observation and treatment);

• inpatient (in settings providing round-the-clock medical observation and treatment).

Primary health care includes:

1) primary pre-medical health care;

2) primary medical health care;

3) primary specialized health care.

Primary health care is provided in outpatient settings.

Primary pre-medical health care in outpatient settings is provided by mid-level medical personnel at feldsher-obstetric stations, maternity hospitals, and primary and secondary vocational education institutions (hereinafter referred to as educational institutions).

Primary medical health care is provided by a district general practitioner or general practice physician (family physician) in outpatient settings. Upon suspicion or detection of an infectious disease in a patient that does not require inpatient treatment based on their health status, the district general practitioner (general practice physicians (family physicians), nursing staff of medical organizations or educational institutions), in the presence of medical indications, refers the patient for consultation to the infectious diseases office of a medical organization to receive primary specialized health care.

Primary specialized health care is provided by an infectious disease specialist.

Specialized, including high-tech, medical care is provided by infectious disease specialists and includes prevention, diagnosis, treatment of diseases and conditions requiring the use of special methods and complex medical technologies, as well as medical rehabilitation.

7. Additional Information

Criteria for an increased risk of an unfavorable outcome in typhoid fever:

• Hospitalization 7 days after the onset of the disease;

• Severe course of typhoid fever;

Signs of an unfavorable course:

• sustained fever type;

• tachycardia;

• arterial hypotension;

• dystrophic myocardial changes;

• anemia;

• leukopenia (less than 3×10⁹ per 1 µl of blood);

• leukocytosis (more than 10×10⁹ per 1 µl of blood);

• possible immunodeficiency state and decreased body resistance, including body weight deficit, history of frequent protracted infections, constitutional developmental abnormalities;

• Chronic comorbidities and chronic focal infection;

• Concomitant infectious diseases.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lira Valeryevna Arslanova – Associate Professor at the Department of Infectious Diseases with Continuing Professional Education Course, Bashkir State Medical University of the Russian Ministry of Health, Candidate of Medical Sciences.

2. Alena Naipovna Burganova – Associate Professor at the Department of Infectious Diseases with Continuing Professional Education Course, Bashkir State Medical University of the Russian Ministry of Health, Candidate of Medical Sciences.

3. Damir A. Valishin – Head of the Department of Infectious Diseases with the Course of Postgraduate Education, Bashkir State Medical University of the Russian Ministry of Health, D.Sc. (Medicine), Professor.

4. Aleksandr V. Gorelov – Academician of the Russian Academy of Sciences, Professor, Chairman of the Management Board of the Academician V.I. Pokrovsky National Association of Infectious Disease Specialists, Deputy Director for Research, Central Research Institute of Epidemiology of Rospotrebnadzor, Head of the Department of Infectious Diseases and Epidemiology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health.

5. Sergey M. Zakharenko – Deputy Director, Children's Research and Clinical Center for Infectious Diseases of the Federal Medical-Biological Agency (FMBA of Russia), Ph.D. (Medicine), Associate Professor.

6. Lidiya A. Kaftyreva – Head of the Laboratory of Intestinal Infections, Pasteur Research Institute of Epidemiology and Microbiology, D.Sc. (Medicine).

7. Zoya N. Matveeva – Leading Researcher, Laboratory of Intestinal Infections, Pasteur Research Institute of Epidemiology and Microbiology, Ph.D. (Medicine).

8. Kseniya E. Novak – Associate Professor, Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, Ph.D. (Medicine).

9. Denis V. Usenko – D.Sc. (Medicine), Executive Director of the Academician V.I. Pokrovsky National Association of Infectious Disease Specialists, Head of the Educational Center, Leading Researcher, Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of Rospotrebnadzor.

10. Vladimir P. Chulanov – Deputy Director for Research and Innovative Development, National Medical Research Center of Phthisiopulmonology and Infectious Diseases of the Russian Ministry of Health, D.Sc. (Medicine), Professor, Professor of the Department of Infectious Diseases, I.M. Sechenov First Moscow State Medical University, Chief freelance specialist in infectious diseases of the Russian Ministry of Health.

11. Liana R. Shaykhullina – Associate Professor, Department of Infectious Diseases with the Course of Postgraduate Education, Bashkir State Medical University of the Russian Ministry of Health, Ph.D. (Medicine).

12. Elena V. Esaulenko – Head of the Department of Infectious Diseases in Adults and Epidemiology, Saint Petersburg State Pediatric Medical University of the Russian Ministry of Health, D.Sc. (Medicine), Professor.

All members of the working group are members of the Pokrovsky National Association of Infectious Disease Specialists (NAIDS).

Appendix A2. Methodology for Developing Clinical Guidelines

1. Infectious disease specialist;

2. General practitioner (internist);

3. Gastroenterologist;

4. General practitioner;

5. Medical students, residents, postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Scale for assessing the levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing the levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision — at least once every three years, as well as upon the emergence of new evidence-based medicine data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ dated November 21, 2011 (as amended on July 2, 2021) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" (with rev. and add., effective July 13, 2021).

2. Federal Law No. 326-FZ dated November 29, 2010 (as amended on February 24, 2021) "On Compulsory Medical Insurance in the Russian Federation", Order of the Ministry of Health and Social Development of Russia No. 541n dated July 23, 2010 (as amended on April 9, 2018).

3. Order of the Ministry of Health and Social Development of Russia No. 541n dated July 23, 2011 "On Approval of the Unified Qualification Handbook of Positions of Managers, Specialists, and Employees, Section 'Qualification Characteristics of Healthcare Worker Positions'", registered with the Ministry of Justice of the Russian Federation on August 25, 2010, registration No. 18247.

4. Sanitary and epidemiological requirements for the prevention of infectious diseases, SanPiN 3.3686–21, dated January 28, 2021, No. 4.

5. Biological and microbiological factors. Bacteriological diagnosis of typhoid fever and paratyphoid fevers A, B, and C. Guidelines (Approved December 29, 2007, No. 0100/13745–07–34).

6. SanPiN 3.3686–21 "Sanitary and epidemiological requirements for the prevention of infectious diseases" XXVII. Prevention of typhoid fever and paratyphoid fevers (Registered with the Ministry of Justice of Russia on February 15, 2021, No. 62500).

7. MU 3.1.3114/1-13. 3.1. Epidemiology. Prevention of infectious diseases. Organization of work in foci of infectious and parasitic diseases. Guidelines (approved by the Chief State Sanitary Doctor of the Russian Federation on October 22, 2013).

8. MU 4.2.2039-05. 4.2. Control methods. Biological and microbiological factors. Technique for collecting and transporting biological materials to microbiological laboratories. Guidelines (approved by Rospotrebnadzor on December 23, 2005).

9. Order of the Ministry of Health of the Russian Federation No. 330 dated August 5, 2003, "On measures to improve therapeutic nutrition in healthcare institutions of the Russian Federation".

10. Order of the Ministry of Health of the Russian Federation No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards".

11. Order of the Ministry of Health of the Russian Federation No. 1008n dated September 23, 2020, "On Approval of the Procedure for Supplying Patients with Clinical Nutrition."

Criteria for assessing the severity of the patient's condition in typhoid fever [1, 2, 3, 4, 5, 11, 12, 18].

Note: ± symptom is inconstant; ++ moderate symptom; +++ pronounced symptom.

Differential diagnosis of typhoid fever with other diseases [1, 2, 3, 4, 5, 11, 12, 18].

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Typhoid fever is a severe infectious disease affecting the gastrointestinal tract, liver, spleen, and blood vessels, characterized by pronounced intoxication. Globally, about 20 million cases and approximately 800 thousand deaths are registered annually.

The causative agent of typhoid fever is the bacterium Salmonella Typhi, which is highly persistent in the environment. In the human body, it produces a potent toxin that determines all symptoms and the severity of the disease. Typhoid fever can be contracted from an infected person or a healthy carrier of the pathogenic bacterium.

Routes of transmission:

• Waterborne – the use of water from surface bodies or industrial process water poses a hazard. This is the most common route. Its risk increases in summer (during swimming in open, sanitarily unsafe water bodies).

• Foodborne – the bacterium survives and multiplies well in milk and meat. Therefore, these products require adequate heat treatment.

• Contact – via household items contaminated with pathogenic microorganisms.

Symptoms of typhoid fever. The incubation period averages 10–14 days, but may range from 3 to 25 days. In the first week of the disease, severe headaches, cough, high fever, chills, loss of appetite, malaise, fatigue, weakness, constipation, and abdominal pain are possible. In the second to third week – high body temperature, diarrhea or constipation, pronounced weakness, weight loss, a painful and enlarged abdomen, and, after the fever subsides, a rash on the chest and abdomen rising above the skin level.

Typhoid fever may be complicated by intestinal hemorrhage, intestinal wall perforation, and subsequent peritonitis. In addition, the disease can lead to the development of pneumonia, thrombophlebitis, cholecystitis, cystitis, myocarditis, as well as parotitis and otitis media.

Treatment of typhoid fever is carried out exclusively in a hospital setting, providing high-quality care and comprehensive treatment including: antibiotic therapy, detoxification, immunotherapy, and diet therapy. With the current level of medical care, the prognosis for typhoid fever is favorable – the disease ends in complete recovery. The prognosis worsens if life-threatening complications mentioned earlier develop.

Non-specific prevention of typhoid fever is the main way to combat this disease. The primary measure is compliance with sanitary and hygienic standards:

• frequent and thorough handwashing,

• boiling water, especially from unreliable sources (at 100°C the pathogen is destroyed instantly),

• boiling milk,

• adequate heat treatment of meat,

• checking the freshness of food products.

Specific prevention of typhoid fever consists of vaccination. Vaccinations are administered according to epidemiological indications in areas endemic for this infection, as well as to individuals traveling to regions and countries with high morbidity or those in regular contact with carriers.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Allgöwer Shock Index

Russian name: Allgower shock index

Original name (if applicable): ___ _________________________________

Source (official developer website, validation publication): [33, 34]:

Type (underline):

- rating scale

- index

- questionnaire

- other (specify): __________________________________________________

Purpose: Determination of blood loss volume

Content (template):

Key (interpretation): Allgower index

(ratio of pulse rate to systolic blood pressure):

0.8 – blood loss volume 10%

0.9–1.2 – blood loss volume 20%

1,3-1,4 – blood loss volume 30 %

1,5 – blood loss volume 40 %

(blood volume in men 5200 ml, in women 3900 ml)

Notes: ____________________________________________________________