Differential diagnosis of exantemas in the clinic of infectious diseases (typhoid fever, meningococcemia, pseudotuberculosis, epidemic typhus). Infectious-toxic shock in clinic of infectious diseases. Problems of “child” infections in adults. Infectious disease of herpesvirus family, their diagnosis and treatment

 

Typhoid fever and paratyphoid

http://wwwnc.cdc.gov/travel/yellowbook/2012/chapter-3-infectious-diseases-related-to-travel/typhoid-and-paratyphoid-fever.htm

Typhoid fever, paratyphoid A and B are an acute illnesses from the group of intestinal infections. They are characterized by cyclic course, bacteremia, intoxication, rash on the skin, lesions of the lymphatic apparatus of the small intestine. Besides that, typhoid  fever  is characterized by high fever of different duration, development of so-called status typhosus, hepatosplenomegaly, lesions of organs of the gastrointestinal tract, relapses and various complications.

History and geographical distribution

Typhoid fever is well known for a long time as an illness of mankind.

The  causative  agent  of  typhoid  fever  was  described  by  Ebert  in  1880. Pure  culture  of  the  agent  was  isolated  by  Gafki  in  1884.

Typhoid  fever  was  one  of  the  most  widespread  and  serious  infectious  disease  in  19^th  century  and  in  the  beginning  of  20-th  century  in  all  countries  of  the  world, especially  in  the  large  towns  due  to  groupment  of  the  people  and  building  of  waterpipe  and  canalization  allowed  to  decrease  morbidity  in  the  large  towns. But  almost  every  calamity (hunger, earthquake)  and  wars  were  accompanied  by  outbreaks  of  typhoid  fever.

Now, the  morbidity  is  sporadic  in  European  countries. However, high  level  of  morbidity  occurs  in  some  countries  due  to  features  of  climate, ecological  conditions  and  social  factors (Mexico, India, Afghanistan, countries  of  Northern  Africa  and  other).

 

Etiology

The causative agent of typhoid  is Salmonella typhi of Enterobacteriacea family, genus Salmonella, serological group D.

Salmonella  are  not-spore-forming  rods and motile  by  peretrichous  flagella (Fig. 1). Like  other  enterobacteria, Salmonella  have  somatic (O) antigens  which  are  lipopolysaccharide  components  of  the  cell  wall  and  flagellar (H) antigens, which  are  proteins. There  are  approximately  60  O-antigens, which  are  designated  by  numbers  at  letters. The  Kauffmann-White  scheme  categorizes Salmonella  on  the  basis  of  somatic  antigens, each  group  having  a  major  determinant  which  is  a  strongly  reaching  somatic  antigens  and  one  or  more  major  somatic  antigen. Salmonella  typhi  also  has  a  capsular  or  virulence (Vi)  antigen  composed  of  a    homopolymer  of  N-acetyl  galactosaminuronic  acid. The  presence  of  Vi-antigen  on  the  cell  surface  may  block  agglutination  by  anti-O serum.

Salmonella typhi

 

Salmonella  can  be  differentiated  from  other  Enterobacteriaceae  on  basis  of  certain  biochemical  reactions, including  fermentation. Most Salmonella ferment glucose and mannose to produce acid and gas but do not ferment lactose or sucrose; S.typhi does not produce gas. Thus, Salmonella  typhi  has  some  antigenic  and  biochemical  features. That is why typhoid  fever  is  isolated  from  the  other  diseases, caused  by Salmonella. Salmonella  organisms  grow  on  the  media  with  addition  of  bile. The  resistance of agent of typhoid fever and paratyphoid  in the environment is very high. They endure low temperatures  very  well. The  agents of typhoid fever and paratyphoid diseases survive from 1-2 till 25-30 days, in food products.

 

Epidemiology

Typhoid  fever  is  anthroponosis. The  source  of  infection  is  sick  man  or  bacteriocarrier. The  patients  with  typhoid  fever  discharge  the  agent  with  stool, urine,  rarely – with  saliva  and  milk. The  discharge  of  the  agent  is  observed  at  the  and  of  incubation  period, during  all  disease, and  sometimes  in  the  period  of  reconvalescence. In  some  cases  the  discharge  continues  till  three  months (acute  carriers) or  more  than  three  months (chronic  carriers). Chronic  carriers  may  be  from  six  months  till  some  years.

The mechanism of the infection transmission  is fecal-oral. The factors of transmission may be water, milk, various food-stuffs and contaminated feces of the patient or bacterial  carriers. Flies can play the supplementary role.

Susceptibility to agent of typhoid fever and paratyphoid diseases is rather high, however clinical manifestation can be of  different grade. The care rate of typhoid fever and paratyphoid diseases depends on seasonal prevalence. It increases in summer-autumn period, due to consumption of a huge amount of flies, quite often from unknown sources, unwashed fruit and vegetables. The strong immunity develops after disease.

 

Pathogenesis

The   next  phases  are  distinguished  in the  pathogenesis  of  typhoid  fever:

1.     Penetration of the  causative agent into the organism.

2.     Development of lymphadenitis and lymphangitis.

3.     Bacteremia

4.     Intoxication.

5.     Parenchymatous diffusion.

6.     Discharge  of  the  agent from the organism (excretory phase).

7.     Allergic reaction, mainly, of lymphoid tissue of the small intestinum.

8.     Formation of immunity.

The first phase is penetration of the agent in the macroorganism. However, penetration  does not always lead to the development of the pathological process. It depends on the quantity of the agent and the state of barrier functions (stomach in this case). The further path of Salmonella typhi is lymphatic apparatus of  intestine.

The second phase is lymphadenitis, lymphangitis. Salmonellae  achieve  the  small  intestine  and  actively  penetrate  into  solitary  follicules, Peyer’s  patches. There  is  the  reproduction  of  the  agents  and  formation  of  the  focus  of  infection. Microorganisms  penetrate  to  regional  lymphatic  nodes (mesenterial)  along  the  lymphatic  patches. There  is  the  other  focus  of  infection. In the lymphatic apparatus, the typical morphological alterations with  proliferation of  tissue and formation  the large typhoid cells develop.

Bacteria   achieve  the  definite  quantity  and enter  into  the  blood  circulation  through  the  thoracic  duct. It  is  the  next  phase  of  pathogenesis –   bacteremia. In  clinic  bacteremia  means  the  end  of  incubation  period  and  beginning  of  the  clinical  manifestations.  The blood has bactericidal properties. It  leads  to  the  death  of  the  part  of microbes. Intoxicative  syndrome  develops. Intoxication is the fourth phase of pathogenesis. The action of endotoxins causes changes of the state of the central nervous system, adynamia, fever, headaches, violations of dream, appetite.

The fifth phase of a pathogenesis is parenchymatous diffusion of microbes. By the flow of the blood Salmonella of typhoid fever and paratyphoid also are delivered over the organism, enter  into all organs. Microbes  are  fixated especially in liver, spleen, bone marrow, skin. Secondary focuses are formed (typhoid granulomas), from which bacteria likewise from the primary focuses (lymphatic apparatus of the intestine) enter  into the blood, supporting bacteremia. The settling of microbes in the reticuloendothelial system and their destruction in the structures of reticuloendothelial system causes  the  cleaning of the organism from  infection.

The sixth phase of  pathogenesis is discharge of  the agent from  the organism. The  agents  enter  into  the  intestine  from  the liver  through  the  bile ducts. They are excreted into the external environment with feces of the patient. The  part  of  the  agents  repeatedly penetrates from  the  small  intestine into  lymphatic apparatus of the intestine and  cause  sensibilization  to  microbes.  The  expressive  changes  of  lymphoid  tissue  develop  due  to  repeated  implantation  of  Salmonella  typhi  with  development  of  morphological  changes  from  cerebral-like  swelling  to  necrosis  and  formation  of  ulcers.

 This process is considered as the seventh phase of pathogenesis – allergic

response of lymphoid tissue of the small intestine.

Eighth phase of pathogenesis is formation of immunity and restoration of the physiological equilibrium.

 

Pathological anatomy

Sequential changes in tissue in the ileocecal area of the intestinal tract occur during typhoid fever and have been classified into four phases:

1. hyperplasia;

2. necrosis and sloughing;

3. ulceration;

4. healing.

During the first week of clinical symptoms, hyperplastic changes occur in Peyer’s patches in the ileum and in lymphoid follicles in the cecum, causing there tissue to project into the bowel lumen. The hyperplasia regresses after 7-10 days or undergoes necrosis with sloughing of overlying mucosa leading to the formation of characteristic ulcers that parallel the long axis of the ileum. Small punctuate lesions develop in the cecum. Ulcers usually heal completely with little residual scarring, but they may be the sites of hemorrhage or may penetrate to the serosa and lead to bowel perforation.

Ulcers of ileum

 

Clinical manifestation

Typhoid  fever  and  paratyphoid  are  characterized  by  cyclic  course. There  are  such  periods  during  course  of  the  infectious  process: incubation, initial, period  of  climax, early  reconvalescence  and  outcomes.

The incubation period of typhoid fever is usually 10-14 days but it may be  from 7 to 21 days. The incubation period is influenced by the number of organisms ingested. The  duration  of  incubation  period  also depends on virulence  of  microorganism  and  state  of  macroorganism.

Manifestations of enterocolitis occasionally occur within hours after the ingestion of food or drink contaminated with S. typhi if the dose of organisms is large. In these instances symptoms of nausea, vomiting and diarrhea usually resolve completely before the onset  of   symptoms  of  typhoid  fever.

The  onset  of  typhoid  fever  is  insidious  in  contrast  to  sepsis  produced  by  most  other  gram-negative  organisms. The  initial  manifestations  are  nonspecific  and  consist  of  fever, malaise, anorexia, headache  and  myalgias. Remittent  fever  is  prominent  with  gradually  increasing  evening  temperature  elevations  from  less  than 38 °C  to  values  in  the  range  of  40 °C  by  the  end  of  the  first  week  of  illness.

Types of temperature curves

The  disease  turns  into  the  next  stage (climax  of  the  disease)  at  the  end  of  the  first  week. The  appearance   of  the  patients  is  very  typical  in  this  period. The  skin  is  pale.  Patient  is  apathethic. Intoxication  is  increased. Temperature  is  constant and  most  typical  syndrome  of  typhoid  fever  and  paratyphoid. At  first  the  temperature  was  described  by  Vunderlish  in  19  century. Temperature  curve  riminds  trapezium. The  phase  of  increase  of  the  temperature  is  near  one  week. The  phase  of  climax  is  near  two  weeks. The  phase  of  decrease  of  the  temperature  is  near  one  week. Temperature  curve  of     Vunderlish  occurs  rarely. Temperature  curve  has  wave-like  character  more  frequently (temperature  curve  of  Botkin).

Chills   and  diaphoreses  are  seen  in  about  one-third  of  the  patient  even  in the  absence of antimicrobial therapy. Either constipation or diarrhea may occur. Respiratory symptoms, including cough and sore throat may be prominent. Neuropsychiatries manifestations, including confusion, dizziness, seizures, or acute psychotic behavior, may be predominant in an occasional case. Status  typhosus  is  observed  in  serious  course  of  the  disease.

In present time patient with typhoid fever usually appears acutely ill. Fever is usually prominent, and in many instances the pulse is slow relative to the temperature.

In  typhoid  fever  symptoms  of  violation  of  cardiovascular  system  are  constant  and  expressive.  The  basis  of  hemodynamic  disorder  is  violation  of  the  tonus  of  the  vessels, damage  of  heart  muscle  due  to  intoxication. Myocardiodystrophy  develops  as  a  result. In  typhoid  fever  relative  bradycardia  is  the  clinical  feature  of  cardiovascular  disorders. The  muffed heart sounds, systolic  murmur  at  the heart  apex, hypotension  are  marked  inrarely. Relative  bradycardia  develops  due  to  endotoxin action  of  the  agent  on X  pair  of  cerebrospinal  nerves.

Rose spots, 2-4 mm erythematous, maculopapular lesions that blanch on pressure, appear on the upper abdomen or on the lateral surface of the body. Roseolas are few (5-15) iumber. The lesions are transient and resolve in hours to days. Rose spots are observed on the 7-10 day of the disease near in half of patients. Sometimes they dissapears, sometimes exist longer than fever.

Cervical lymphoadenopathy may be present.  Examination of the chest may reveal moist rales. The abdomen is tender, especially in the lower quadrants. Abdominal distention is common, and peristalsis is often hypoactive. The sensation of displacing air – and fluid-filled loops of bowel on palpating of the abdomen is considered to be characteristic. In percussion short sound is marked in ileocaecal area due to enlarged mesenteric lymphatic nodes (Padalka symptom).

Rose spots

Hepatomegaly is noted in about 40-50 % of the patient, and a soft, tender spleen  can be palpated in about 40-60 %. In about 10 % of the patients, changes in consciousness are present and manifest as lethargy, delirium, or coma.

Without antimicrobial therapy, the disease pursues a prolonged course with slow resolution of signs and symptoms 3-4 weeks after onset if there are no complications. Sustained fever is common during the second and third weeks of disease. Fever decreases slowly by lysis, unlike the resolution by crisis seen in the preantibiotic era in many cases of pneumococcal pneumonia. Headache, confusion, respiratory symptoms, and abdominal pain and distention gradually resolve, and the pulse more characteristically reflects degree of fever acute manifestations subsiding. Profound weight loss invariably occurs in untreated patient. Many of the complications of typhoid  fever occur during the period of resolution in the third or fourth week after onset.

Complications

Complications of typhoid fever can be classified as secondary to toxemia (myocarditis, hyperpyrexia, hepatic and bone marrow damage), secondary to local gastrointestinal lesions (haemorrhage and perforation), secondary to prolonged severe illness (suppurative parotitis decubiti, and pneumonia), secondary to growth and persistence of typhoid fever bacilli (relapse, localized infection – meningitis, endocarditis, osteomyelitis or arthritis – and secondary to therapy (bone marrow suppression, hypersensitive reactions and toxic shock).

In the preantimicrobial era, 12-16 % of the patients with typhoid fever died, frequently from complications in the third or fourth week of the disease. Fatalities still occur occasionally, probably in less than one percent of the patients receiving appropriate antimicrobial and pathogenetic  therapy. However, in certain specific geographic areas of Indonesia, India, and Nigeria, fatality rations of 9-32 % have been reported last 10-15 years. It is likely that these results are consequent to suboptimal health and medical care rather that an increase in the clinical severity of typhoid fever.

The complications attributed to “toxemia” might be considered as manifestations of severe disease. Toxic myocarditis occur in severely ill patients, frequently children, and is manifested by tachycardia, weak pulse, muffled heart sounds, and hypotension. The electrocardiogram shows low voltage and T-wave flattening or inversion. Atrial or ventricular arrhythmia may occur.

Major intestinal hemorrhage is usually a late complication that occur during the second or third week of illness. In the preantimicrobial era, gross intestinal hemorrhage occurred in about 5-7 % of the patient with typhoid fever. The incidence of hemorrhage requiring transfusions has been reduced to 1 or 2 %, due to chloramphenicol use. There  is  an  important  sign  of  the  massive  intestinal  hemorrhage  symptom  of  “scissors”. Suddenly  the  temperature  is  decreased  up to  normal  or  subnormal. But  tachycardia   is  observed. The  arterial  pressure  is  reduced. Intestinal perforation usually occurs during third week of illness. Perforation  occurs in  the  terminal  ileum  where  the  number  of  lymphoid  aggregates  is  the largest  and  ulcerations  most  frequent. In  general, perforation  has  reported  in  recent  years  in  one  percent  or  less  of  cases  as  compared  with  2-5 %  in  several  series  collected  in  the  preantibiotic  era.

 

Decreasing of temperature and tachycardia (“scissors” symptom)

Relapse, a recurrence of the manifestation of typhoid fever after initial clinical response, occur in about 8-12 % of the patient who have not received antimicrobial therapy. The relapse rate was found to be doubled in patients receiving chloramphenicol therapy  for 2 weeks. Ampicillin probably does not affect the rate of relapse.

Localization of infection, which may lead to abscess formation, can occur in almost any organ or tissue. Although bacteremia can be assumed to develop in all patient with typhoid fever, localized infections such as meningitis, endocarditis, osteomyelitis, or thyroiditis occur in less then one percent.

The chronic carrier state is detained as documented excretion of S. typhi in stool or urine for a year or more. The chronic carrier state usually follows typhoid fever but as many as one – third of the chronic carriers give no history consistent with this illness. Underlying biliary or urinary tract diseases, especially with stone formation, increase the probability of the chronic enteric or urinary carrier state in   patients with typhoid fever. One to 3 % of the patients with typhoid fever become chronic enteric carriers; however, the incidence is higher in older patients (at the sixth decade) and in women.

 

Clinical features of paratyphoids

Epidemiology, pathogens, morphology and clinics of paratyphoid A and B, have, in principal, mutual signs with typhoid fever. However, paratyphoids have some clinical features.

In paratyphoid A incubation period is shorter than in typhoid fever. It’s duration is 8-10 days. The onset of the disease is an acute. Sometimes, the onset of the disease is accompanied by cough, catarrh. Facial hyperemia, blood injection of the sclera’s vessels, herpes on the lips are observed during examination. The temperature is wave-like or remittent. The fever is accompanied by chills and than by diaphoreses. In paratyphoid A the rash appeares in more early periods than in typhoid fever. The rash is polymorphic. Roseolas, petechias and measles-like rash may be observed. The intoxication is temperate. There is no status typhosus. There is normal quantity of leukocytes in peripheral blood. But leukocytosis and lymphocytosis may occur too.

In majority of the patients the disease has a moderate course. But the severe forms may  be observed too, with complications (intestinal hemorrhage, intestinal perforation and other). The relapses are frequently observed in case of   paratyphoid A.

Paratyphoid B incubation period is 5-10 days. The onset of the disease is acute, with expressive chill, myalgia and diaphoreses. At the initial period of the disease the intoxication may be combined with symptoms of acute gastroenteritis. The temperature is not prolonged. Status typhosus is absent in majority of the patients. The symptoms of intoxication disappeares very quickly. The rash is polymorphic, plenty. It  appears at the earlier period. In some cases the course of paratyphoid B may be severe with septic manifestations (purulent meningitis, meningoencephalitis, septicopyemia). In peripheral blood leukocytosis and neutrophylosis are observed.

 

Diagnosis

Definitive diagnosis of typhoid fever and paratyphoid  is made on the basis of pathogen isolation from the patient’s blood. Isolation of the organism from stool, especially in endemic areas, does constitute strong presumptive evidence of typhoid fever in the patient with a typical clinical course. Serologic studies may be helpful, but in many cases of typhoid fever there is no increase in titer of agglutinins during the course of infection, and other illnesses, especially infections with other gram – negative bacilli, may cause nonspecific elevations of agglutinins because of cross – reaching antigens. In untreated disease only about 50 %  of the patient have a fourfold or greater increase in titer of agglutinins (Vidal’s test) against typhoid fever 0 antigen at any time during the course of disease.

 Antimicrobial therapy may also impede immunologic response. Immunization with typhoid fever vaccine may produce an impressive increase in titer of anti-0 agglutinins and nonspecific changes in titer may occur during the course of many febrile illnesses.  Agglutinins against H antigen, irrespective of change of titer, are not of value in diagnosis. A number of other serodiagnostic methods, defection of IgM antibody to S. typhi lipopolysaccharide antigen by an enzymelinked immunosorbent assay (ELISA), are being studied and seen promising, but none is ready for routine diagnostic use.

The majority of isolates of S. typhi from blood are obtained as a result of the first blood culture, but a second or third culture should be collected in suspected cases, as these culture significantly improve the percentage of positives. Stool cultures become positive in about one – third to two – thirds of the patients during the second through fourth week of illness.

 

Differential diagnosis

The differential diagnosis of typhoid fever requires consideration of many disease processes characterized by fever and abdominal complaints.

Early in the disease the predominance of fever and upper respiratory tract symptoms may suggest influenza or other viral infections. Cough and fever suggest acute bronchitis and, when coupled with rales, raise the question of bacterial pneumonia. Headache, confusion, and fever may prompt consideration of bacterial or aseptic meningitis or meningoencephalitis. Delirium, catatonia, or coma may suggest a diagnosis of psychosis or other neuropsychiatries illness. The abdominal findings may lead to a consideration of acute appendicitis, acute cholecystitis, or intestinal infarction. Bacillary, amebic or ischemic colitis may enter the differential diagnosis if blood diarrhea occurs. As fever continues over a period of weeks, other possibilities might include brucellosis, yersinosis, lymphoma, inflammatory bowel disease, bacterial endocarditis, miliary tuberculosis, malaria, sepsis, epidemic typhus and many other diseases.

Treatment

http://www.rightdiagnosis.com/p/paratyphoid_fever/intro.htm

Antibacterial therapy is indicated to all patients. The basic preparation is Levomycetin (Chloramfenicole) in tablets  0.5. It is indicated inside on 0.5 (4 times per day for half an hour before meal till the 10-th day of body temperature stabilization, a daily dose is reduced usually till 1.5 on the last 4 – 5 days of treatment. At severe course of illness it is possible to increase a daily dose gradually, on first days Levomycetin should be taken up to 3 gm, but not more. If using of the Levomycetin (PO) is impossible (a nausea, vomiting, a pain in epigastric area) Levomycetin succinate in bottles 0.5 (IM) daily dose 3 – 4 gm or in suppositoriums should be prescribed, and in serious cases  intravenous or endolymphatic  0.5 – 1 ( 2 times in days) application.

When there is no effect after using of Levomycetin during next 5 days and there are  contraindications, that is effective to prescribe Ampicillin till the 10-th day of normal body temperature. Alternative preparations may be Bactrim, Azitromicin (Sumamed) and fluoroquinolones preparations Ciprofloxacin and Ofloxacin  to which  steady to Levomycetin stames are sensitive. Also may be used cefalosporines of III generation: Cefoxim or Ceftriaxone.

To prevent relapses and formation of chronic bacteriocarrier the antibiotic therapy is desirable for carrying out in a complex with Vi-antigen, stimulating creation of specific immunity. Preparation of typhoid bacteria is injected on 400 mgm under a skin on 7 days interval or twice the same dose, or 800 mgm on 10 days interval.

Plentiful drinking, sorbents (SКN, VЕSТА), Sillard P, Enterodes are prescribed as desintoxication agents at mild disease course. Solution of glucose (IV) with solution of ascorbic acid, Qurtasault, Acesole, Lactasole, a solution of donor Albumin are injected at moderate disease course. If process has severe course, Reopolyglycin is  injected both with polyionic colloid solutions at increasing of  intoxication for 7 days, Prednisolonum 30-60 mg and more per day parenterally during 5–7 days. Oxybarotherapy, Plasmaferesis are indicated. Inhibitors of proteolytic enzymes – Contrical, Gordoxe, Trasylole should be prescribed.

Obligatory components of complex therapy are  bed regime and diet № 2. For stimulation of nonspecific organism resistance and reparative process there are indicated Methyluracil, Pentoxil, Thimalin.

 During antibiotic therapy the intestinal dysbacteriosis may be  developed. Nistatin or Levorin one of bacterial preparations Bificol, Bifidumbacterin, Lactobacterin are indicated in such cases. If allergical reactions have appeared, Calcy gluconate, Dimedrol, Diprazin, Tavegil, Gismanal, Zestra, Loratidin, Alegra, Telfast are indicated.

A strict confinement to bed (position of the patient on back), cold on stomach region, forbiding reception of nutrition on 10 – 12 hours are necessary at intestinal bleeding. There are indicated ascorbic acid in tablets, Vicasole, Calcy chlorid, hypertonic solution of Sody chloride 5-10 mL (I.V.), Aminocapronicy acid, Etamsylat, Adroxone, Gelatinole, infusions of the donor blood, saline solutions.

The immediate surgical operation is indicated in case of intestinal wall perforation. Dofamin,  high doses of Prednisolone,  Reopolyglycin, Qurtasole or Lactasole in a vein trickle and then trickling (a single dose 0.05-0.15 gm, in serious cases up to 0.4 gm) in isotonic solution of Sodium chloridum, Contricali are indicated too in case of infectional-toxic shock. 

Treatment of chronic bacteriocarrier is not developed. It is possible to achieve the time termination of allocation salmonelas by realization of 10-day’s course of treatment by Ampicillin in a daily dose of 2 gm in combination with immunostimalatores and di- or  monovalent vaccine in a combination with cleared Vi-antigen.

 

Prophylaxis

http://cid.oxfordjournals.org/content/45/Supplement_1/S24.full

Control of Salmonella typhi infection transmitted from person to person depends on high standards of personal hygiene, maintenance of a supply of uncontaminated water, proper sewage dispose and identification, treatment, and follow-up of chronic carriers. Hand washing is of paramount importance in controlling person – to person spread although hands of convalescent carriers are often contaminated after defecation detectable Salmonella are easily removed by washing the hands with soap and water.

Typhoid fever vaccine, a saline suspension of aceton or heat/phenol killed S. typhi enhances the resistance of human beings to infection with S. typhi under experimental and natural conditions. Vaccine efficacy ranges from 51 to 67 %.

There is also renewed interest in testing the capsular polysaccharide of S. typhi (Vi antigen) as a parenteral typhoid fever vaccine.

Typhoid fever vaccine should be considered for persons with intimate continuing exposure to a documented typhoid fever carrier and for persons traveling to areas where there is a recognized appreciable risk to exposure to typhoid fever.

EPIDEMIC TYPHUS FEVER

http://extension.entm.purdue.edu/publichealth/diseases/louse/typhus.html

 

Synonyms – jail fever; ship fever; putrid fever; petechial fever; typhus exanthematicus.

Definition

Epidemic  typhus fever is an acute infections disease caused by Rickettsia Prowazeki. Epidemic  typhus  fever  is  characterized  by  development  of  generalized  thrombovasculitis, meningoencephalitis, severe  common  intoxication, by  appearance  of  rash,  increased  lever  and  spleen. It is transmitted by the louse, Pediculus humanus.

History  and  geographical  distribution

Epidemic  typhus fever has been one of the great epidemic diseases of the world. Its history belongs to the dark pages of the world’s story, at times when war, famine and misery of every kind are present.

The disease was first described with sufficient accuracy by  Frascastoro, in the 16th century, to enable us distinctly to differentiate it from plaque; the stuporous states of the two disease having previously caused them to be confounded.

Epidemics of typhus have very frequently been  associated with war. In fact, severe epidemics have occurred during practically every great war in Europe with the exception of the Franco-Prussion war in 1870. In the World War, the epidemic which raged in Serbia in 1915 was one of the most severe which has                                                                                                                                                 occurred in modern times. It was characterized not only by its high virulence and high mortality. During the epidemia  the number of new fever cases entering the military hospitals alone, reached as high as 2500 per day, and the number of reported cases among the civilian population was approximately three times was this number. The mortality during the epidemic varied during the epidemic at different periods in different localities between 30 and 60 %. Over 150.000 deaths occurred within 6 months, before  the epidemic could be suppressed. An astonishing 30 million cases occurred in Russia and Eastern Europe during 1918 – 1922, with an estimated 3 million deaths. During World War II, typhus struck heavily in concentration camps in Eastern Europe and in North Africa.

In the present time this disease may be occurs in Africa (Burundi, Ethiopia), in the Central America (Mexico, Peru).

Etiology

The etiologic agent is Rickettsia Prowazekii, an obligate intracellular bacterium that is closely related antigenically to the agent that causes murine typhus (Rickettsia typhi). The organism is cocobacillary but has inconstant morphologic characteristics. Reproduction is by binary fission and diplobacilli are produced that are frequently seen in tissue sections. Special staining (Giemsa) provides good visualization of the organisms in the cytoplasm of cells.

Rickettsia Prowazekii

 

Epidemiology

The source of infection is a sick man. Epidemic typhus (or louse-borne typhus) is transmitted from person to person by the body louse (Pediculus humanus corporis) (Fig. 6). The louse feeds on an infected, rickettsemic person. The organism in the louse infects its alimentary tract and results in large numbers of organisms in its feces within about 4-5 days. Close personal or clothing contact is usually required to transmit lice to others. When the louse takes a blood meal, it defecates. The irritation causes the host to scratch the site, thereby contaminating the bite wound with louse feces. Human infection might also occur by mucous membrane inoculation with contaminated louse feces.

 

 

Pediculus humanus corporis

Human conditions that foster the proliferation of lice are especially common during winter and during war or natural disasters – where in clothing is not changed, crowding occurs, and bathing is very infrequent.

In  epidemic  the  susuptibility   is  high  for  all  age  groups.

 

Pathogenesis  and  Morbid  Anatomy

After local proliferation  at the  site of the louse bite, the organism spreads hematogenously. Rickettsia Prowazekii, as  with  most  rickettsia, produces a vasculitis by infecting  the  endothelial  cells  of  capillaries,  small  arteries,  and veins. The process results in fibrin and platelet deposition and then occlusion of the vessel. Perivascular infiltration with lymphocytes, plasma cells, histiocytes, and polymorphonuclear leukocytes occurs with or without frank necrosis of the vessel. The angiitis is most marked in the skin, heart, central nervous system, skeletal muscle, and kidneys.

The  mechanism of the development of epidemic typhus may be represented by the next phases:

1.     Penetration of Rickettsia Prowazekii into organism and reproduction in the endothelial cells of the vessels.

2.     Destruction  of  endothelial  cells  and  penetration of  rickettsia  into  the  blood – rickettsiemia, toxinemia.

3.     Functional  violations  of  the  vessels  in all organs and tissues – vasodilatation, slowdoun of the stream of the blood.

4.     Destructive  and  proliferative  alterations  of  the  capillaries  with  formation specific  granulemas (nodules).

5.     Formation of immunity.

Small hemorrhages in the conjunctivae are frequent. The heart usually shows slight gross changes. Microscopically the blood vessels show similar lesions to those observed in the skin, and sometimes there is considerable infiltration with mononuclear and polymorphonuclear cells. Thrombi are rarely found in the larger blood vessels.

The blood is usually duck colored and liver and kidneys show cloudy swelling. The spleen is somewhat enlarged during the early stages of the disease but tends to be normal in size later on. It is often very soft and then may rupture from being handled at autopsy. Microscopically, engorgement with blood, with extensive phagocytosis of red blood corpuscles and diminution of lymphoid elements, is commonly present.

The lesion in the brain, particularly in the basal ganglia, medulla and cortex of the cerebrum, and more rarely in the white matter and cerebellum, correspond in size to miliary tubercles and are secondary to lesions of the small blood vessels and capillaries, as in the skin. They first consist of a collection of large cells of vascular and perivascular origin, endothelium, and monosytes, with necrosis resulting from occlusion of the vessel.

 

Clinical manifestations

Epidemic typhus is cyclic infectious disease. There are the next periods in the course of the disease: incubation period (it’s duration is from 6 till 25 days). Initial period till appearance of the rash (it’s duration is 4-5 days), period of climax – from appearance of rash till normalization of the temperature (it’s duration is from 4-5 days till 8-10 days) and period of reconvalescence (it’s duration is 2-3 weeks).

After an incubation period an abrupt onset with intense headache chills, fever and myalgia is characteristic. There is no eschar. The fever worsens quickly and becomes unremitting and the patient is soon prostrated by the illness. Giddiness, backache, anorexia, nausea are observed in the patients. The appearance of the patient is typical. The face is edemaous, flushed. Eyes are brilliant with injected sclera (“rabbit’s eyes”). Enanthema (small hemorrhages) on the basis of uvula is marked on the second or third day of the disease (symptom of Rosenberg). The petechial rash may be revealed on transitive folds of conjunctiva from the third-forth day (symptom of Kjary-Aucyne). the early sign is tremor of the tongue, it’s declining to the side (symptom Govorov-Godeljae) due to bulbaric disorders. Splenomegaly is marked on the 3-4 day of the disease in the majority of the patients.

 

 

 

 

Patient with epidemic typhus

 

 Injected sclera (“rabbit’s eyes”)

 

Climax period is characterized by development of all clinical manifestations of the disease. The temperature is definite high level (febris remittans). Temperature decreases frequently on the 3-4, 8-9 and 12-13 day of the disease and than the temperature increases again. Climax period is accompanied by intoxication and damage of central nervous system.

The appearance of the rash is an important sign of climax period. A rash begins in the axillary folds and upper part of the trunk on about the fifth day of illness and spread centrifugally. Initially, the rash consists of nonconfluent, pink macules that fade on pressure, may be rose- and petechial like. Within several days, the rash becomes maculopapular, darker, petechial and confluent and involves the entire body, palms and solls but never the face. Disappear with decreasing of temperature.

 

Petechial-like rash

 

The Circulatory System. Very outspoken is cardiac weakness due to myocardial degeneration. The heart sounds are very weak and the pulse feeble, rapid and irregular. The blood pressure often is very low, especially the diastolic, and may remain so throughout the disease. Bradycardia may be marked during convalescence.

The Respiratory System. Cough may appear in the first days, but usually is first troublesome about the time of the eruption. By the end of a week, the cough becomes loose and rales of various types may be noted.

The Alimentary Tract.  Constipation is usually noted. Very marked is the tendency of the mouth and  tongue to become dry and sordes to collect on the teeth. It is often difficult to get the patient to protrude his tongue when told to do so. In the patients with epidemic typhus splenomegaly and hepatomegaly (from one second week) are marked.

 

 Maculopapular rash

 

The Nervous System. Clouding of the consciousness may be as marked in this disease. Dull aching frontal headache is common and is an early predominating symptom. It frequently diminishes before the eruption appears. A dull stuporous state soon comes on. Delirium is marked in some cases. There are often the faces and mental state of alcoholic intoxication. There may be meningitis, meningoencephalitis.

In  epidemic  typhus  fever  it  may  be  leucocytosis, neutrophylosis, monocytosis  in  the  blood. ESR  is  accelerated.

The  variants  of  the  course  of  the  disease

 There  are  mild, moderate  and  serious course  of the  epidemic  typhus  fever. During  the  light  course  of  the  disease  the  occurrences  of  intoxication  are  expressed  insignificantly. The  temperature increases till  38 °C.  The consciousness  is  no  changed. The  rash  predominates  as  roseoles. The  liver  and  spleen  increases  in the  third  patients. The  duration  of  fever  is  till  9  days. The  mild  course  is  observed  in  10-20 %  patients.

The  medium  serious  course  of the  disease  occurs  more  frequently  (60-65 %  patients). The  temperature increases till  38-39 °C. The  duration  of  the  fever  is  12-14 days. The  signs  of  the  intoxication  are  expressed  temperate.

During  the  serious course  of  the  epidemic  typhus  fever  expressive  intoxication, hypotonia, tachycardia ( till 140 in  minute) are  observed.  The  tones  of  the  heart are  deaf. There  is  acrocyanosis. The  dyspnea  occurs, it  may  be  violation  of  the  rhythm  of  the  breathing. The  cramps of  the  muscles, the  violation  of  the  swallowing  are  marked. The  temperature increases till  40-41 °C. The  rash  is  petechial, it  may  be  hemorrhage. The  serious  course  occurs  in  10-15 %  patients. The  serious  and  very  serious  course of  the  disease  takes  place  in elderly  people. 

Complications

Bronchitis, pneumonia otitis media, parotitis, nephritis, tromboses of various vessels, both abdominal and peripheral may be present.

Diagnosis

  The methods of the laboratory diagnostic are serological: indirect hemagglutination, indirect immunofluorescens, complement fixation. During the  period  of onset of the diseasethe  differential  diagnosis  is  performed  with  grippe, pneumonia, meningitis, hemorrhagic  fevers. During  the  period  of  the  climax  the  differential  diagnosis  is performed with  typhoid  fever, ornithosis, drug  disease, leptospirosis, infectious  mononucleosis, trichinellosis. 

Treatment

http://health.nytimes.com/health/guides/disease/typhus/overview.html

The  treatment  of  the  patient  is  complex: etiotropic, pathogenetic  and symptomatic.

Etiotropic therapy. Chloramphenicol and  tetracycline are  more  effective  in  epidemic  typhus. The  recommended  dose  for  tetracycline  is  0.3-0.4g, chloramphenicol – 0.5g  four  times  per  day. Usually  antibiotics  are  abolished  from  the  third  day  of  the  normal  temperature.

Pathogenetic  therapy  includes  heart  (corglycon, strophantin) and  vascular (cordiamin, ephedrine, mezaton) remedies. During  the  serious  course the  disintoxicative  and  dehydrative  therapy  is  performed. Sometime  during  the  case  of  expressive  exciting  bromides, aminaszin, barbiturates, seduxen  are  prescribe. The  patients  may  walk  from 7-8  day  of  the  normal  temperature. The  discharge  of  the  patients  from  the  hospital  may  be  realized  at  12  day  of  the  normal  temperature.

Prophylaxis

http://www.umm.edu/ency/article/001363prv.htm

Control of the human body louse and the conditions that foster its proliferation is the mainstay in preveting louse-borne typhus.

Typhus vaccine is prepared from formaldehyde-inactivated Rickettsia Prowazekii grown in embryonated eggs. Typhus vaccination is suggested for special risk group.

BRILL-ZINSSER  DISEASE

http://www.rightdiagnosis.com/b/brill_zinsser_disease/intro.htm

Brill-Zinsser disease occurs as a recrudescence of previous infection with Rickettsia Prowazekii. It occurs in the United States primarily in immigrants from Eastern Europe whose initial infection was early.

Brill-Zinsser disease is acute cyclic disease. It  is endogenic relapse of epidemic typhus. Brill-Zinsser disease is characterized by sporadic morbidity in absence of louse.

In Brill-Zinsser disease the pathogenesis and morbid anatomy are similar epidemic typhus, however the process is less expressive, because the concentration of rickettsia Prowazekii is similar in the blood. The course of Brill-Zinsser disease is more light than epidemic typhus, but the patients have all typical symptoms of the disease.

Initial period (it’s duration is 3-4 days) is accompanied by temperate intoxication. Headache, disorder of sleep, increase of the temperature till 38-39° are marked. Enanthema is observed rarely (in 20% of the cases). The duration period is usually 5-7 days. It is characterised by temperate hyperthermia (38-39°) of remittent or rarely constant type.

The sighs of the damage of the central nervous system are expressed temperately. Meningeal sighs are revealed rarely.

A rash is observed in 60-80% of the patients. The sighs of the damage of the cardiovascular system  are marked frequently. Enlarged liver and spleen are revealed inconstantly.

In Brill-Zinsser disease the complications develop rarely. It may be pneumonia, thrombosis, thrombophlebitis.

The treatment is the same as in epidemic typhus.

The differentiation of primary louse-borne typhus is made by showing that the antibody produced is IgM (primary louse-borne) or IgG (Brill-Zinsser disease).

 

DIAGNOSTICALLY-MEDICAL WORK

The early exposure of infectious patients matters very much for giving timely medical assistance, especially at the severe course of infectious disease, development of complications which require urgent  therapy (infectic-toxic shock, brain edema and other like that). It is necessary to notice that the complex of antiepidemic measures begins after the revealing of infectious patient (inspection of contacts, current and final desinfection, urgent prophylaxis).

The active, timely and complete revealing of all infectious and vermin patients belongs to the duties of IC doctor, and also bacterio- and parasite carriers, their treatment and hospitalization. That is why attention is paid on quality and plenitude of clinical and laboratory inspection of patients, which have the protracted fever, persons which suffers from  hepatitis, cholecystitis and others like that. The individual cards of out-patients and register of account of housings visits are regularly checked up.

Component part of diagnostics is a clinical picture of illness and sequence of development of its symptoms, ability to find out among them resistant symptoms and syndromes. Lately diagnosed viral hepatitis, typhoid or other infectious diseases – it’s often due to inattention to the initial symptoms of illness. Recognition of modern infectious diseases, in consideration of plenty of latently running and effaced forms, especially in the early period of their development is combined with some difficulties and only careful comparison of all clinical, data of epidemiologist and laboratory, and also results of specific researches allows to put a timely and correct diagnosis.

IC doctor does not replace district doctors and doctors of out-patient’s clinics which are central figures in the early and complete revealing of infectious patients, but gives them skilled help. He gives the same consultative help to the doctors of other specialties: to the surgeons, oncologists, gynecologists and other, if they treat patients with suspicion on an infectious disease. Patients are directed by them for inspection at IC with the individual card of out-patient, in which must be marked a district doctor or doctor of other specialty, anamnesis of life, anamnesis of illness, results of review and previous diagnosis. In all such patients diagnostic-laboratory inspection is necessary to confirm or eliminate infectious nature of illness.

At a necessity, with the purpose of clarification of diagnosis, setting of treatment-prophylactic measures and decision about hospitalization, a IC doctor must give consultative help to the district internists and doctors of other specialties, examine patients at home, but only after consultation with head of department. The promoted attention is deserved to patient with long lasting fever. They must be under  supervision every day and not later than  third day of illness examined the head of therapeutics department, and at a necessity – by IC doctor. At presence of fever five days and longer a patient must be hospitalized in infectious hospital.

All patients with the protracted fever it is necessary to check laboratory for the exception of typhoid and paratyphoid, spotted fever, malaria, leptospirosis, and at presence of the proper epidemiological anamnesis – for other infectious and vermin diseases.

  The work a IC doctor must be constantly under supervision of district doctors of diagnostic value of the carefully collected epidemiological anamnesis and detailed clinical inspection, and also application, at a necessity, different laboratory and instrumental methods of examination. i.e. , for diagnostics of viral hepatitis most value has an revealing of activity of aminotransferases and markers of hepatitis in the  of blood. It is important that the increase of activity of these enzymes appears already at the end of latent period and at the beginning of illness, before the appearance of characteristic clinical signs, including jaundice, in most contagious period of hepatitis. A substantial diagnostic value for recognition of illness has revealing of biliary pigments in urine.

In case of intestinal infections, taking into account their different etiology and similar clinical symptoms, during the inspection of persons which have disorders of bowels, a doctor must apply all accessible methods for establishment of correct etiologic diagnosis, namely: clinical with the obligatory review of emptying, bacteriological, serological, instrumental.

The most reliable results gives the bacteriological method of examination. The material for this method can be vomiting mass, water of stomach, emptying, and food in case of toxic-food infections. For greater probability for receiving  positive results, material for laboratory research must be taken before etiotropic treatment. The best results get  bacteriological research and mainly in those cases, when conducted directly in a policlinic. Material for sowing is sent for revealing of Shigellosis, Salmonellosis (including typho-paratyphoid group),Escherichia, Staphylococcus and other bacteria. However, the negative results of such research do not eliminate infectious nature of disease. Except for researches on the exposure of bacterial flora, it is necessary to conduct research for the presence of viruses which often are reason of diarrhea, and also the simplest.

A selection and authentication of viruses is carried out in the specialized laboratories. Correct sampling, storage and delivery of material have a large value for virology research. The methods of virology of diagnostics of infectious diseases are more difficult, than bacteriological. To select viruses, chicken embryos, cultures of cells and fabrics, laboratory animals are use. The cultures of cells are needed also for determination of cytopathic effect based on  destruction of the cells infected by virus, and also for conducting of reactions of neutralization (RN), hemadsorbtion and others.

          Serological methods of research are based on the revealing of antibodies to the agents of infectious diseases or their antigens. Use of different reactions, more frequent reaction of agglutination (RА) – Vidal’s for typhoid and paratyphoid, Rayta and Heddlsona for Brucelosis , agglutinations of rickets– for spotted fever; reaction of non direct hemagglutination, reaction of hemagglutination inhibition. For diagnostics of viral illnesses more frequent is used  a radioimmune analysis (RIA), immunoenzyme analysis (ІEА). In these reactions the high titles of antibodies or their growth in 4 times and anymore have a diagnostic value in research of paried serum, taken with an interval  7-14 days.

The results of different methods of research (clinical, biochemical, bacteriological, serological, virology) are used for the estimation of severity, control after the process of convalescence, determination of terms of discharge of patients from permanent establishment and duration of ambulatory treatment and clinical supervision.

Rectoromanoscopy is one of the type of research, which is included in the complex of inspection of patients with dominant signs of the defeat of colon. Rectoromanoscopy is especially indicated for recognition of the not clear, atypical forms of illness,, and also except an acute course of disease as a control of efficiency of treatment and by plenitude of clinical and morphological convalescence.

Coprologic as well as rectoromanoscopic examination, is used as a additional method, as the changes found out here are not specific, but only specify on the morphological and functional changing in bowels. These methods have most value in the conditions of policlinic, so as allow quickly to discover inflammatory changes in a colon and send a patient in permanent establishment for a subsequent inspection and treatment. A coprologic method can be used for diagnostics of helminthes and protozoic collitis.

The biopsy of liver is used for diagnostics, differential diagnostics of liver diseases and control after efficiency of therapy of viral hepatitis.

Ultrasound research (USG) is used for diagnostics of diffuse and focal defeats of liver, kidneys, pancreas, and also for diagnostics of biliary and kidney stones diseases.

The doctor of cabinet can conduct together with a district internist or domestic doctor treatment at home of patients with shigellosis, flu and other infectious diseases, and also bacteriocarriers which with permission from epidemiologist or other reasons are not hospitalized (mild course of illness, to insulate at home, refusal of patient from hospitalization and others). Such patients are visited at home by a district internist or domestic doctor, and on occasion doctor-infectionist. In every case IC doctor must give consultative help in relation to treatment and conduct the systematic looking after a patient and persons which he lives with. Modern facilities of  ethiotropic, patogenetic and symptomatic therapy are used. In a period reconvalescence, when it is already possible to visit a policlinic, subsequent looking after him, completing the curation and control of patient by doctor-infectionist who decides about admitting to work after final clinical and laboratory convalescence.

For an example point recommendations for treatment in the ambulatory terms of patient with shigellosis and therapies of other intestinal infections.

A doctor to which a patient appealed with complaints about dysfunction of bowels must conduct measures for clarification of etiology of illness with the use for this purpose of accessible methods of inspectioamely: clinical with a review emptying, coprologic, bacteriological methods of research. A control after registration of patient and timely diagnostics depends upon a IC doctor. After establishment of primary diagnosis, till the receipt of results of bacteriological research, the doctor of cabinet together with an epidemiologist must decide a question about expedience of hospitalization of patient.

Patients with shigellosis are subject for obligatory hospitalization after clinical and epidemiologist testimonies: the severe and moderate course of disease, presence of severe accompanying diseases, age (children up to 3 y.o., sloping and senile), patient or his family members which belong to the decreed groups of population, residences with children, which goes to preschool establishments, absence at home conditions for support of the antiepidemic mode, residence of hostels, persons which arrived from cholera regions.

If a patient is not hospitalized, at home it is necessary to conduct current disinfections forces of relatives of patient. To beginning of treatment ethiotropic agents a doctor or medical sister is conduct to collect material from a patient for coprologic and bacteriological research for the presence of shigellosis, salmonella, pathogenic bacteria and serologic research.

Treatment in home conditions to liquidation of acute displays of illness is provided by district internist, but all settings conform to the doctor-infectionist. On a 5th day from the beginning of treatment an additional inspection is conducted by IC doctor in the conditions of policlinic; he conducts a control after convalescence and decides the question of admittance to work.

Treatment must be strictly individual, early and complex, with the use of ethiotropic facilities, polyenzymes (festal, kreon, pankumer), antioxidants, polyvitamines. Application of antibiotics now is not obligatory at the mild and effaced course of illness. Usually  preparations of nitrofurantine deliveries (furagin, furazolidon, nifuroxazid) are used. Use oral rehydration mixtures (glucosolan, rehydron,cytroglucosolan,gastrolit).    Disintoxicative  enterosorbents are used during 3-5 days after 1,5-2 h before or after meal. Bacterial preparations which normalize intestinal microflora are used (bifiform,bifikol,biosporyn,coli- and bifidumbacterin).

Reconvalescent is admitted  to work not earlier than  in 3 days after normalization of emptying and body temperature. Patients with bacteriological confirmation of diagnosis conduct non-permanent control of bacteriological research of emptying. Expedient is conducting of rectoromanoscopy for normalization of mucus picture of distal  segment of colon.

During the epidemic of flu it is very important to give effective medical help to population, to prevent development of complications. In this period a policlinic work according to special plan. Home medicare is given by district internists and family doctors, and at a necessity to this work other doctors are attracted. Ambulatory reception of patients with a flu can conduct the specialists of narrow specialty under a control of an experienced internist.

A IC doctor must inspect patients for parasites-carrying, using the scrab method (enterobiosis). District internists, with consultatory help of doctor of cabinet, conduct treatment of patients with helmiths invasion.

A doctor of IC must systematically provide the analysis of treatment-diagnostic work with lighting of the followings questions:

1)         term of establishment of diagnosis of infectious disease from the beginning of disease to the day of appeal for medical help;

2)         term of hospitalization after separate conditions from the beginning of illness and from a moment of appeal for medical help;

3)          usage of laboratory methods of research for confirmation of diagnosis;

4)         coinciding of diagnosis with an eventual diagnosis, set in permanent establishment.

The analysis of treatment-diagnostic work of IC cabinet for a year must be added to the annual report.

ORGANIZATION OF DISPENSARY CARE AFTER ACUTE INFECTIOUS DISEASES

AND PATIENTS WITH CHRONIC INFECTIONS

The results of clinical supervision together with the results of analyses A doctor of IC organizes the clinical care after reconvalescents, patients with chronic pathology, bacterio- and parasites- carriers and conducts their treatment.

Reconvalescents from infectious diseases discharge from permanent establishment with the “unclosed” medical certificate, which is continued in a policlinic.

The purpose of clinical supervision consists of prevention of relapses of illness, passing to the chronic form, timely diagnostics of relapses and chronic course, revealing of barcterio- and parasite- carriers, hospitalization of these categories of people. The ultimate goal of clinical supervision is to renew work ability and its saving, providing of the proper quality of life, prophylaxis of disability.

The special attention is deserved to pregnant with infectious pathology, as the row of pathogens can cause intrauterine  infections of fetus with development of structural defects in many organs and systems of organism, especially in the central nervous system and, even, his death. The so-called TORCH-infections belong to these illnesses, namely: T – of toxoplasmosis; O-(others) – other, from which absolutely proved : syphilis, chlamydiosis, hepatitis, gonococcus and enteroviral infections; – measles, epidemic parotitis, possible –; hypothetical is a flu, papillomas, caused by viruses, lymphocytic choriomeningitis; R – rubeolla, C- cytomegaloviral  infection; H- herpes.

 (bacteriological, serological, biochemical) are brought in the ambulatory card of patient. On the title page of ambulatory card a conventional sign is put: reconvalescents after carried dysentery – “D”, after viral hepatitis is a triangle of brown color with the date of disease and date of discharge from permanent establishment. Conventional signs are made to pay attention of doctors and use every visit of patient for a duty review both, in the set terms, and later, especially those, who was ill viral hepatitis, for the exposure of late complications.

At the primary review of persons which are subject for clinical supervision, a doctor must write down complaints and data of objective examination of patient in an ambulatory card. By analysis and estimation of laboratory findings it is necessary to draw up clearly diagnosis and work out a plan of treatment-prophylactic measures.

A doctor of IC must constantly conduct the detailed analysis of results of the clinical care after reconvalescents and bacterio- and parasite carriers.

A removal from  clinical account is conducted by commission composed with of doctor of infectious diseases, epidemiologist and head of policlinic. An obligatory condition for a removal from clinical account is complete convalescence of patient, which is determined by a complex inspection. To the healthy people belongs persons without complaints in the moment of review and the signs of the remaining disease are not marked after the carried illness, and also indexes of laboratory inspections are within the limits of norm.

 

Infectious-toxic shock

Toxic shock syndrome (TSS) is a potentially fatal illness caused by a bacterial toxin. Different bacterial toxins may cause toxic shock syndrome, depending on the situation. The causative bacteria include Staphylococcus aureus, where TSS is caused by enterotoxin type B, and Streptococcus pyogenes. Streptococcal TSS is sometimes referred to as toxic shock-like syndrome (TSLS) or streptococcal toxic shock syndrome (STSS).

Initial description

The term toxic shock syndrome was first used in 1978 by a Denver pediatrician, Dr. James K. Todd, to describe the staphylococcal illness in three boys and four girls aged 8–17 years. Even though S. aureus was isolated from mucosal sites in the patients, bacteria could not be isolated from the blood, cerebrospinal fluid, or urine, raising suspicion that a toxin was involved. The authors of the study noted reports of similar staphylococcal illnesses had appeared occasionally as far back as 1927, but the authors at the time failed to consider the possibility of a connection between toxic shock syndrome and tampon use, as three of the girls who were menstruating when the illness developed were using tampons. Many cases of TSS occurred after tampons were left in the person using them.

Rely tampons

Following controversial test marketing in Rochester, New York and Fort Wayne, Indiana, in August 1978, Procter and Gamble introduced superabsorbent Rely tampons to the United States market in response to women’s demands for tampons that could contain an entire menstrual flow without leaking or replacement. Rely used carboxymethylcellulose (CMC) and compressed beads of polyester for absorption. This tampon design could absorb nearly 20 times its own weight in fluid.[12] Further, the tampon would “blossom” into a cup shape in the vagina to hold menstrual fluids without leakage.

In January 1980, epidemiologists in Wisconsin and Minnesota reported the appearance of TSS, mostly in those menstruating, to the CDC. S. aureus was successfully cultured from most of the subjects. The Toxic Shock Syndrome Task Force was created and investigated the epidemic as the number of reported cases rose throughout the summer of 1980. In September 1980, CDC reported users of Rely were at increased risk for developing TSS.

On 22 September 1980, Procter and Gamble recalled Rely following release of the CDC report. As part of the voluntary recall, Procter and Gamble entered into a consent agreement with the FDA “providing for a program for notification to consumers and retrieval of the product from the market.” However, it was clear to other investigators that Rely was not the only culprit. Other regions of the United States saw increases in menstrual TSS before Rely was introduced.

It was shown later that higher absorbency of tampons was associated with an increased risk for TSS, regardless of the chemical composition or the brand of the tampon. The sole exception was Rely, for which the risk for TSS was still higher when corrected for its absorbency. The ability of carboxymethylcellulose to filter the S. aureus toxin that causes TSS may account for the increased risk associated with Rely.

Epidemiology

Staphylococcal toxic shock syndrome is rare and the number of reported cases has declined significantly since the 1980s. Patrick Schlievert, who published a study on it in 2004, determined incidence at 3 to 4 out of 100,000 tampon users per year; the information supplied by manufacturers of sanitary products such as Tampax and Stayfree puts it at 1 to 17 of every 100,000 menstruating people per year.

The CDC has stopped tracking TSS. However, there was a rise in reported cases in the early 2000s: eight deaths from the syndrome in California in 2002 after three successive years of four deaths per year, and Schlievert’s study found cases in part of Minnesota more than tripled from 2000 to 2003. Schlievert considers earlier onset of menstruation to be a cause of the rise; others, such as Philip M. Tierno and Bruce A. Hanna, blame new high-absorbency tampons introduced in 1999 and manufacturers discontinuing warnings not to leave tampons in overnight.

Signs and symptoms

Symptoms of toxic shock syndrome vary depending on the underlying cause. TSS resulting from infection with the bacterium Staphylococcus aureus typically manifests in otherwise healthy individuals with high fever, accompanied by low blood pressure, malaise and confusion, which can rapidly progress to stupor, coma, and multiple organ failure. The characteristic rash, often seen early in the course of illness, resembles a sunburn, and can involve any region of the body, including the lips, mouth, eyes, palms and soles. In patients who survive the initial phase of the infection, the rash desquamates, or peels off, after 10–14 days.

In contrast, TSS caused by the bacterium Streptococcus pyogenes, or TSLS, typically presents in people with pre-existing skin infections with the bacteria. These individuals often experience severe pain at the site of the skin infection, followed by rapid progression of symptoms as described above for TSS. In contrast to TSS caused by Staphylococcus, streptococcal TSS less often involves a sunburn-like rash.

For Staphylococcal toxic shock syndrome, the diagnosis is based strictly upon CDC criteria modified in 1997 after the initial surge in tampon-associated infections.:

Body temperature > 38.9 °C (102.02 °F)

Systolic blood pressure < 90 mmHg

Diffuse rash, intense erythroderma, blanching

Desquamation (especially of the palms and soles) 1 – 2 weeks after onset.

Involvement of three or more organ systems:

Gastrointestinal (vomiting, diarrhea)

Muscular: severe myalgia or creatine phosphokinase level at least twice the upper limit of normal for laboratory

Mucous membrane hyperemia (vaginal, oral, conjunctival)

Renal failure (serum creatinine > 2 times normal)

Hepatic inflammation (AST, ALT > 2 times normal)

Thrombocytopenia (platelet count < 100,000 / mm³

CNS involvement (confusion without any focal neurological findings)

Negative results of:

blood, throat, and CSF cultures for other bacteria

negative serology for Rickettsia infection, Leptospirosis, and Measles.

Cases are classified as confirmed or probable based on the following:

• Confirmed: All six of the criteria above are met (unless the patient dies before desquamation can occur)
• Probable: Five of the six criteria above are met.

Pathophysiology

In both TSS (caused by S. aureus) and TSLS (caused by S. pyogenes), disease progression stems from a superantigen toxin that allows the nonspecific binding of MHC II with T cell receptors, resulting in polyclonal T cell activation. In typical T cell recognition, an antigen is taken up by an antigen-presenting cell, processed, expressed on the cell surface in complex with class II major histocompatibility complex (MHC) in a groove formed by the alpha and beta chains of class II MHC, and recognized by an antigen-specific T cell receptor.

By contrast, superantigens do not require processing by antigen-presenting cells but instead interact directly with the invariant region of the class II MHC molecule. In patients with TSS, up to 20% of the body’s T cells can be activated at one time. This polyclonal T-cell population causes a cytokine storm, followed by a multisystem disease. The toxin in S. aureus infections is TSS Toxin-1, or TSST-1. The TSST-1 is secreted as a single polypeptide chain.

The gene encoding toxic shock syndrome toxin is carried by a mobile genetic element of S. aureus in the SaPI family of pathogenicity islands.

Treatment

The severity of this disease frequently warrants hospitalization. Admission to the intensive care unit is ofteecessary for supportive care (for aggressive fluid management, ventilation, renal replacement therapy and inotropic support), particularly in the case of multiple organ failure. The source of infection should be removed or drained if possible: abscesses and collections should be drained. Anyone wearing a tampon at the onset of symptoms should remove it immediately. Outcomes are poorer in patients who do not have the source of infection removed.

Antibiotic treatment should cover both S. pyogenes and S. aureus. This may include a combination of cephalosporins, penicillins or vancomycin. The addition of clindamycin or gentamicin reduces toxin production and mortality.

 

HERPETIC DISEASES

 

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as human herpesvirus 1 and 2 (HHV-1 and HHV-2), are two members of the herpesvirus family, Herpesviridae, that infect humans. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus. Herpes Simplex can be spread through contact with saliva, such as sharing drinks.

Symptoms of herpes simplex virus infection include watery blisters in the skin or mucous membranes of the mouth, lips or genitals. Lesions heal with a scab characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system in the cell bodies of neurons. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron’s axon to the skin, where virus replication and shedding occur and cause new sores.

TEM micrograph of a herpes simplex virus.

Transmission

HSV-1 and -2 are transmitted by contact with an infected area of the skin during re-activations of the virus. Although less likely, the herpes viruses can be transmitted during latency. Transmission is likely to occur during symptomatic re-activation of the virus that causes visible and typical skin sores. Asymptomatic reactivation means that the virus causes atypical, subtle or hard to notice symptoms that are not identified as an active herpes infection. Daily genital swab samples show that HSV-2 is found in a median of 12-28% of days among those who have had an outbreak and 10% of days among those suffering from asymptomatic infection, with many of these episodes occurring without visible outbreak (“subclinical shedding”). For HSV-2, subclinical shedding may account for most of the transmission, and one study found that infection occurred after a median of 40 sex acts. Atypical symptoms are often attributed to other causes such as a yeast infection. HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing and mouth-to-genital contact (oral sex). HSV-2 is primarily a sexually transmitted infection but rates of HSV-1 genital infections are increasing.

Both viruses may also be transmitted vertically during childbirth, although the real risk is very low. The risk of infection is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother gets the virus for the first time during late pregnancy.

Herpes simplex viruses can affect areas of skin exposed to contact with an infected person. An example of this is herpetic whitlow which is a herpes infection on the fingers. This was a common affliction of dental surgeons prior to the routine use of gloves when conducting treatment on patients.

Viral structure

Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large double-stranded, linear DNA genome encased within an icosahedral protein cage called the capsid, which is wrapped in a lipid bilayer called the envelope. The envelope is joined to the capsid by means of a tegument. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames, ORFs) within their genomes, although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus. These genes and their functions are summarized in the table below.

The genomes of HSV-1 and HSV-2 are complex and contain two unique regions called the long unique region (U_L) and the short unique region (U_S). Of the 74 known ORFs, U_L contains 56 viral genes, whereas U_S contains only 12. Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host. Immediate early genes, which encode proteins that regulate the expression of early and late viral genes, are the first to be expressed following infection. Early gene expression follows, to allow the synthesis of enzymes involved in DNA replication and the production of certain envelope glycoproteins. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.

Five proteins from (U_L) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.

Cellular entry

Entry of HSV into the host cell involves interactions of several glycoproteins on the surface of the enveloped virus, with receptors on the surface of the host cell. The envelope covering the virus particle, when bound to specific receptors on the cell surface, will fuse with the host cell membrane and create an opening, or pore, through which the virus enters the host cell.

The sequential stages of HSV entry are analogous to those of other viruses. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell. In the case of a herpes virus, initial interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to a cell surface particle called heparan sulfate. A second glycoprotein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These include herpesvirus entry mediator(HVEM), nectin-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules. Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid. Glycoprotein B interacts with glycosaminoglycans on the surface of the host cell.

A simplified diagram of HSV replication

Replication

Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, are produced. Research using flow cytometry on another member of the herpes virus family, Kaposi’s sarcoma-associated herpesvirus, indicates the possibility of an additional lytic stage, delayed-late. These stages of lytic infection, particularly late lytic, are distinct from the latency stage. In the case of HSV-1, no protein products are detected during latency, whereas they are detected during the lytic cycle.

The early proteins transcribed are used in the regulation of genetic replication of the virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-early transcription. The virion host shutoff protein (VHS or UL41) is very important to viral replication. This enzyme shuts off protein synthesis in the host, degrades host mRNA, helps in viral replication, and regulates gene expression of viral proteins. The viral genome immediately travels to the nucleus but the VHS protein remains in the cytoplasm.

The late proteins are used in to form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the genome, core and the capsid – occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by cleavage and are placed into pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles.

Micrograph showing the viral cytopathic effect of HSV (multi-nucleation, ground glass chromatin).

Latent infection

HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia. HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacral ganglia, but note that these are tendencies only, not fixed behavior. During such latent infection of a cell, HSVs express Latency Associated Transcript (LAT) RNA. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or “outbreaks” characteristic of non-latency. Whether or not recurrences are noticeable (symptomatic), viral shedding occurs to produce further infections (usually in a new host, if any). A protein found in neurons may bind to herpes virus DNA and regulate latency. Herpes virus DNA contains a gene for a protein called ICP4, which is an important transactivator of genes associated with lytic infection in HSV-1. Elements surrounding the gene for ICP4 bind a protein known as the humaeuronal protein Neuronal Restrictive Silencing Factor (NRSF) or human Repressor Element Silencing Transcription Factor (REST). When bound to the viral DNA elements, histone deacetylation occurs atop the ICP4 gene sequence to prevent initiation of transcription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle. Another HSV protein reverses the inhibition of ICP4 protein synthesis. ICP0 dissociates NRSF from the ICP4 gene and thus prevents silencing of the viral DNA.

The virus can be reactivated by illnesses such as colds and influenza, eczema, emotional and physical stress, gastric upset, fatigue or injury, by menstruation and possibly exposure to bright sunlight.

Treatment and vaccine development

Herpes viruses establish lifelong infections, and the virus cannot yet be eradicated from the body. Treatment usually involves general-purpose antiviral drugs that interfere with viral replication, reduce the physical severity of outbreak-associated lesions, and lower the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as acyclovir and valacyclovir can reduce reactivation rates.

 

MENINGOCOCCAL INFECTION

http://www.nlm.nih.gov/medlineplus/meningococcalinfections.html

Definition

 Meningococcal  infection  is  an  acute  infectious  disease  of  the  human,  caused  by  meningococcous  Neisseria Meningitigis. The  mechanism  of  the  transmission  of  the  infection  is  air-drop. The  disease  is  characterized     by  damage  of  mucous  membrane  of  nasopharynx (nasopharingitis),  generalization   of  the  process in  form  of  specific  septicemia (meningococcemia) and  inflammation  of  the  soft  cerebral membranes (meningitis).

Epidemiology

The importance of meningitis disease is as significant in Africa as HIV, TB and malaria. Cases of meningococcemia leading to severe meningoencephalitis are common among young children and the elderly. Deaths occurring in less than 24-hours are more likely during the disease epidemic seasons in Africa and Sub-Saharan Africa is hit by meningitis disease outbreaks throughout the epidemic season. It may be that climate change contributes significantly the spread of the disease in Benin, Burkina Faso, Cameroon, the Central African Republic, Chad, Côte d’Ivoire, the Democratic Republic of the Congo, Ethiopia, Ghana, Mali, Niger, Nigeria and Togo. This is an area of Africa where the disease is endemic: meningitis is “silently” present, and there are always a few cases. When the number of cases passes five per population of 100,000 in one week, teams are on alert. Epidemic levels are reached when there have been 100 cases per 100,000 populations over several weeks.

Further complicating efforts to halt the spread of meningitis in Africa is the fact that extremely dry, dusty weather conditions which characterize Niger and Burkina Faso from December to June favor the development of epidemics. Overcrowded villages are breeding grounds for bacterial transmission and lead to a high prevalence of respiratory tract infections, which leave the body more susceptible to infection, encouraging the spread of meningitis. IRIN Africa news has been providing the number of deaths for each country since 1995, and a mass vaccination campaign following a community outbreak of meningococcal disease in Florida was done by the CDC.

The distribution of meningococcal meningitis in Africa

Pathogenesis

In  meningococcal  infection  entrance  gates  are  mucous  membrane  of  nasopharynx. It  is  place  of  primary  localization  of  the  agent. Further  meningococci  may  persist  in  epithelium  of  nasopharynx  in  majority  of  the  cases. It  is  manifested  by  asymptomatic  healthy  carriers. In  some  cases  meningococci  may  cause  inflammation  of mucous  membrane  of  upper  respiratory  tract. It  leads  to  development  of  nasopharingitis.

 The  localization  of  meningococcus  on  mucous  membrane  of  nasopharynx  leads  to  development  of  inflammation  in  10-15 %  of  the  cases.

The  stages  of  inculcation  on  the  mucous  membrane  of  nasopharynx  and  penetration  of  meningococcus  into  the  blood  precede  to  entrance  of  endotoxin  into  the blood  and  cerebrospinal  fluid. These  stages  are  realized  with  help  of  factors  of  permeability. It  promotes  of  the  resistance  of  the  meningococcus  to  phagocytosis  and  action  antibodies.

Meningococci  are  able  to  break  local  barriers  with  help  of  factors  of  spread (hyaluronidase). Capsule  protects  meningococci  from  phagocytosis. Hematogenous  way  is  the  principal  way  of  the  spread  of  the  agent  in  the  organism (bacteremia, toxinemia). Only  the  agent  with  high  virulence  and  invasive  strains  may  penetrate  through  hematoencephalitic  barrier. The  strains  of serogroup A high  invasivicity.

 Meningococci  penetrate  into  the  blood  after  break  of  protective  barriers  of  mucous  membrane  of  upper  respiratory  tract. There  is  hematogenous  dissemination (meningococcemia). It  is  accompanied  by  massive  destruction  of  the  agents  with  liberation  of  endotoxin. Meningococcemia  and  toxinemia  lead  to  damage  of  endothelium  of  the  vessels. Hemorrhages  are  observed  in  mucous  membrane, skin  and  parenchymatous  organs. It  may  be  septic  course  of  meningococcemia  with formation of the secondary metastatic focuses in the endocardium, joints, internal mediums of the eyes.

In most of the cases penetration of meningococci in the cerebrospinal fluid and the soft cerebral covering is fought about by hematogenous ways through the hematoencephalic barrier. Sometimes meningococci may penetrate into the skull through perineural, perilymphatic and the perivascular way of the olfactory tract, through the enthoid bone.

Thus the meningococci enter into subarachnoid space, multiply and course  serous-purulent and purulent inflammation of the soft cerebral coverings. The inflammatory process is localized on the surface of the large craniocerebral hemispheres, and rarely, on  the  basis, but sometimes it may spread in the covering of the spinal cord. During severe  duration of the inflammatory process the cranium is covered by purulent mather (so-cold  “purulent  cap”). It  may  lead  to  involvement  of  the  brain’s  matter  into  inflammatory  process  and  meningoencephalitis.

The process may engulf the rootlets of – VII, VIII, V, VI, III and XII pairs of cranial nerves.

Pathogenic  properties  of  the  agent, state  of  macroorganism, state  of  immune  system, functional  state  of  hematoencephalitic  barrier  have  the  meaning  in  the  appearance  of  meningitis  of  any  etiology.

Endothelium  of  capillaries, basal  membrane, “vascular  pedicles”  of  glyocytes  and  basic  substance  of  mucopolysaccharide  origin  are  the  morphologic  basis  of  hematoencephalic  barrier. Hematoencephalic barrier  regulates  metabolic  processes  between  blood  and  cerebrospinal  fluid. It  realizes  protective  function  from  the  alien  agents  and  products  of  disorder  of  metabolism. The  most  alterations   are  observed  in  reticular  formation  of  the  middle  brain.

 In  purulent  meningitis some  pathogenic  moments  are  promoted  by  rows  of  paradoxical  appearances  in hematoencephalic  barrier  and  membranes  of  the  brain. In  physiological  conditions hematoencephalic  barrier  and  brain’s  membranes  create  closed  space, preventing  brain’s  tissue  from  influence  of  environment. In  this  case  secretion  and  resorbtion  of  cerebrospinal  fluid  are  proportional. In  meningitis  closed  space  leads  to  increased  intracranial  pressure  due  to  hypersecretion  of  cerebrospinal  fluid  and  to  edema  of  the  brain. The  degree  of  swelling-edema  of  the  brain  is  decisive  factor  in  the  outcome  of  the  disease.

The  next  stages  may  single  out  in  pathogenesis  of  purulent  meningitis:

1.     Penetration  of  the  agent  through hematoencephalic  barrier, irritation  of  receptors  of  soft  cerebral  membrane  of  the  brain  and  systems, forming  cerebrospinal  fluid.

2.     Hypersecretion  of  cerebrospinal  fluid.

3.     Disorder  of  circulation  of  the  blood  in  the  vessels  of  the  brain  and  brain’s  membranes, delay  of  resorbtion  of  cerebrospinal  fluid.

4.     Swelling-edema  of  the  brain  hyperirritation  of  the brain’s  membranes  and  radices  of  cerebrospinal  nerves.

Besides  that, intoxication  has  essential  meaning  in  pathogenesis  of  purulent  meningitis. Vascular  plexuses  and  ependime  of  ventricles  are  damaged  more  frequently. Then  the  agent  enters  in  to  subarachnoid  space  and  brain’s  membranes  with  the  spinal  fluid  flow.

In some cases, especially  in  increated patients the  process may  turn  into  ependima  of  the  ventricles. As  a  result  it  may  be  occlusion  of  the  foramina  of Lushka, Magendie, the  aqueduct of Sylvius. It leads to development to hydrocephaly.

In the pathogenesis of meningococcal infection toxic and allergic components play an important role. Thus, in  fulminate  forms  of  meningococcal  infection  infectious-toxic  shock  develops  due  to  massive  destruction  of  meningococcus  and  liberaton  of  considerable  quantity  of  endotoxin. In  infectious-toxic  shock  the  development  of  thrombosis, hemorrhages, necrosis  in  different  organs  are  observed  even  in  the  adrenal  glands (Waterhause – Fridrechsen  syndrome).

The  severe  complication  may  develop  as  a  result  of  expressive  toxicosis. It  is  cerebral  hypertension, leading  frequently  to  lethal  outcome, cerebral  coma. This  state  develops  due  to  syndrome  of  edema  swelling  of  the  brains with  simultaneous  violation  of  outflow  of  cerebrospinal  fluid  and  its  hyperproduction. The  increased  volume  of  the  brain  leads  to  pressure  of  brain’s  matter, its  removement  and  wedging  of  medulla  oblongata  into  large  occipital  foramen, pressure  of  oblong  brain, paralysis  of  breath  and  cessation  of  cardiovascular  activity.

The disease’s pathogenesis is not fully understood. The pathogen colonises a large number of the general population harmlessly, but thereafter can invade the blood stream and the brain, causing serious illness. Over the past few years, experts have made an intensive effort to understand specific aspects of meningococcal biology and host interactions, however the development of improved treatments and effective vaccines will depend oovel efforts by workers in many different fields.

The incidence of endemic meningococcal disease during the last 13 years ranges from 1 to 5 per 100,000 in developed countries, and from 10 to 25 per 100,000 in developing countries. During epidemics the incidence of meningococcal disease approaches 100 per 100,000. There are approximately 2,600 cases of bacterial meningitis per year in the United States, and on average 333,000 cases in developing countries. The case fatality rate ranges between 10 and 20 per cent.

While meningococcal disease is not as contagious as the common cold (which is spread through casual contact), it can be transmitted through saliva and occasionally through close, prolonged general contact with an infected person.

Meningococcal disease causes life-threatening meningitis and sepsis conditions. In the case of meningitis, bacteria attack the lining between the brain and skull called the meninges. Infected fluid from the meninges then passes into the spinal cord, causing symptoms including stiff neck, fever and rashes. The meninges (and sometimes the brain itself) begin to swell, which affects the central nervous system.

Even with antibiotics, approximately 1 in 10 victims of meningococcal meningitis will die; However, about as many survivors of the disease lose a limb or their hearing, or suffer permanent brain damage. The sepsis type of infection is much more deadly, and results in a severe blood poisoning called meningococcal sepsis that affects the entire body. In this case, bacterial toxins rupture blood vessels and can rapidly shut down vital organs. Within hours, patient’s health can change from seemingly good to mortally ill.

The N. meningitidis bacterium is surrounded by a slimy outer coat that contains disease-causing endotoxin. While many bacteria produce endotoxin, the levels produced by meningococcal bacteria are 100 to 1,000 times greater (and accordingly more lethal) thaormal. As the bacteria multiply and move through the bloodstream, it sheds concentrated amounts of toxin. The endotoxin directly affects the heart, reducing its ability to circulate blood, and also causes pressure on blood vessels throughout the body. As some blood vessels start to hemorrhage, major organs like the lungs and kidneys are damaged.

Patients suffering from meningococcal disease are treated with a large dose of antibiotic. The systemic antibiotic flowing through the bloodstream rapidly kills the bacteria but, as the bacteria are killed, even more toxin is released. It takes up to several days for the toxin to be neutralized from the body by using continuous liquid treatment and antibiotic therapy.

Meningococcemia (meningococcal sepsis)

The disease is more impetuous, with symptoms of toxicosis and development of secondary metastatic foci. The onset  of  the disease is an acute. Body temperature may increase upto 39-41 ⁰C and lasts for 2-3 days. It  may be continous, intermittent, hectic, wave-like. It is possible the course of the disease  without  fever. There  is  no  accordance  between  degree  of  increasing  of  the  temperature  and  severity  of  the  course  of  the  disease.

The  other  symptoms  of  intoxication  arise  simultaneously  with  fever: headache, decreased  appetite  or  its  absence, general  weakness, pains  in  the  muscles  of  the  back  and   limbs. Thirst, gryness  in  the  mouth, pale skin or cyanosis, tachycardia   and  sometimes  dysphnoea  are  marked. The  arterial  pressure increases  in  the  beginning  of  the  disease. Then  it decreases. It  may  be  decreased  quantity  of  urine. Diarrhea  may  be  in  some  patients. It  is  more  typical  for  children.

Exanthema  is  more  clear, constant  and  diagnostically  valuable  sign  of  meningococcemia.

 Exanthema in case of meningococcemia

 Dermal  rashes  appear  through 5-15  hours, sometimes  on  the  second  day  from  the  onset  of  the  disease. In  meningococcal  infection  rash  may  be  different  over  character,  size  of  rash’s  elements  and  localization. Hemorrhagic  rash  is  more  typical (petechias, ecchymosis  and  purpura).

The  elements  of  the  rash  have  incorrect (“star-like”) form, dense, coming  out  over  the  level  of  the  skin. Hemorrhagic   rash  is  combined  inrarely  with  roseolous and  papulous  rash.

The  severe  development  of  the  rash  depends  from  the  character, size  and  depth  of  the  its  elements.  The  deep  and  extensive  hemorrhages  may  be  necrosed. Then  it  may  be  formation  of  deep  ulcers. Sometimes  deep  necrosis  is  observed  on  the  limbs  and  also, necrosis  of  the  ear, nose  and  fingers (Fig. 5)  of  the  hands  and  legs.

 

 Necrosis of fingers

 Zones of leg necrosis

During  biopsy  meningococci  are  revealed. Exanthema  is  leucocytaric-fibrinous  thrombosis, contained  the  agent  of meningococcal  infection. Thus, in  meningococcal  infection  rash  is  the  secondary  metastatic  foci  of  the  infection.

Joints  occupy  the  second  place  over  localization  of  metastases  of  the  agent. At  the  last  years  arthritises    and  polyarthritises  are  marked  rarely  (in  5 %  of  the  patient  during  sporadic  morbidity  and  in  8-13 %  of  the  patient  during  epidemic  outbreaks). The  small  joints  are  damaged  more  frequently. Arthritis  is  accompanied  by  painful  motions, hyperemia  and  edema  of  the  skin  over joints.

Arthritises  appear  later  then  rash  (the end  of  the  first  week – the beginning  of  the  second  week  of  the  disease).

 Secondary  metastatic  foci  of  the  infection  may  appear  rarely  in  the  vascular  membrane  of  the  eye, in  myocardium, endocardium, lungs  and  pleura. Similar  foci  arise  very  rarely  in  kidneys, liver, urinary  tract, borne  marrow.

In  the  peripheral  blood  high  leukocytosis, neuthrophillosis  with  shift   of  the  formula  to  the  left  aneosinophyllia,    increased  ESR  are  observed. Thrombocytopenia   develops inrarely.

There  are  alterations  in  urine  as  during  syndrome  of  “infectious-toxic  kidneys”. Proteinuria, microhematuria, cylinderuria are marked.

Meningococcal sepsis is combined with meningitis in majority cases. In  4-10 %  of  the  patients  meningococcemia  may  be  without  damage  of  the  soft  cerebral  covering. Frequency  of  meningococcal  sepsis  is  usually  higher  in  the  period  of  epidemic.

Fulminate meningococcemia ( acutest meningococcal sepsis, Waterhause-Friedrichen syndrome)

It is the more severe, unfavorable  form  of  meningococcal infection. Its base  is  infectious-toxic shock. Fulminate sepsis is  characterized  by  acute sudden beginning and impetuous  course. Temperature of body rises up to 40-41 ^oC. It is accompanied by chill.   However, hypothermia  may  be observed  through  some  hours. Hemorrhagic  plentiful  rash  appears  at  the  first  hours  of  the  disease  with  tendency  to  confluence  and  formation  large  hemorrhages, necroses. A purple-cyanotic spots arise on the skin (“livors mortalis”). The  skin is pale, but with a total cyanosis. Patients are anxious and excited. The  cramps  are  observed  frequently, especially in children. The recurrent blood vomiting  arise  inrarely. Also, a bloody diarrhea  may be  too. Gradually, a prostration becomes more excessive and it results is a loss of the consciousness.

Heat’s  activity decreases  catastrophically. Anuria  develops (shock’s  kidney). Hepatolienalic  syndrome  is  revealed  frequently. Meningeal  syndrome  is  inconstant.  

In  the  peripheral  blood  hyperleukocytosis (till 60*10⁹/l), neutrophylosis, sharp shift  leukocytaric  formula  to  the  left, thrombocytopenia, increased  ESR (50-70 mm/h)  are  reveled. The  sharp  disorders  of  hemostasis  are  marked –  metabolic  acidosis, coagulopathy  of  consumption, decrease  of  fibrinolitic  activity  of  the  blood  and  other.

Mixed  forms (meningococcemia + meningitis)

These forms occur in 25-50 % cases of generalized meningococcal infection. In  the last years there is tendency of increase frequency of mixed forms in general structure of the disease, especially in periods of epidemic outbreaks. It is characterized by combination of symptoms of meningococcal sepsis and damage of cerebral membranes.

Rare forms of meningococcal infections

These  forms (arthritis, polyarthritis, pneumonia, iridocyclitis) are consequence of meningococcemia. Prognosis is favorable   in  opportune  and  sufficient  therapy.

Diagnostics

The diagnosis of all forms of meningococcal infection is based on the complex of epidemiological and clinical data. The  final  diagnosis  is  established  with  help  of  the  laboratory  examination. Separate  methods have different diagnostical significance in various clinical forms of meningococcal infections.

 The  diagnosis of meningococcal carrier is possible only by use of bacteriological method. The  material for analysis is the mucus from proximal portions of upper respiratory tract. In diagnostics of meningococcal nasopharyngitis epidemiological and bacteriological methods occupy  the  main  place. Clinical  differention of meningococcal nasopharyngitis from nasopharyngitis of the  other genesis is no possible or very difficult.

In recognition of generalized forms, anamnestical and clinical methods of diagnostics have real diagnostic significance, mainly in combination of meningococcemia and meningitis.

 The  examination  of  cerebrospinal  fluid (CSF)  has  great  meaning  in   diagnostics  of  meningitis. In  lumbar  punction cerebrospinal  fluid  flows  out  under  high  pressure  and  by  frequent  drops. The cerebrospinal  fluid  may  flow  out  by  rare  drops  only  due  to  increased  viscosity  of  purulent  exudation  or  partial  blockade of  liquor’s  ways. Cerebrospinal  fluid  is  opalescent  in  initial  stages  of  the  disease. Then  it  is  turbid, purulent, sometimes  with  greenish  shade.

 Cerebrospinal  fluid  in meningococcal meningitis

Pleocytosis  achieves till  10-30 10³  in  1  mcl. Neuthrophils  leukocytes  predominate  in  cytogram. Neuthrophilous  compose  60-100%  of  all  cells. In  microscopy  neuthrophils  cover  intirely  all  fields  of  vision, inrarely. Quantity  of  protein  of  cerebrospinal  fluid increases  (till  0,66-3,0 g/l). There  is  positive  Nonne-Appelt’s  reaction. The  reaction  of  Pandy  composed (+++). Concentration  of  glucose  and  chlorides  are  usually  decreased.

In  generalized forms  the  final  diagnosis  is  confirmed  by  bacteriological  method. In  diagnostics  immunological  methods  are  used too. Reactions of  hemagglutination, latex  agglutination  are  more  sensitive.

 

Differential  diagnosis

 In  meningococcemia  the  presence  of  rash  requires  of  differential  diagnostics  with  measles, scarlet  fever, rubella, diseases  of  the  blood (thrombocytopenic  purpura Werlgoff’s  disease; hemorrhagic  vasculitis – Sheinlein-Henoch’s  disease).   Sometimes  it  is  necessary  to  exclude  epidemic  typhus, grippe, hemorrhagic  fevers.

It  is  necessary  to  differentiate  meningococcal  meningitis  with  extensive  group  of  the  diseases:

1.     Infectious  and  noninfectious  diseases  with  meningeal  syndrome  but  without  organic  damage  of  central  nervous  system (meningismus). Meningismus  may  be  in  grippe, acute  shigellosis, uremia, lobar  pneumonia, toxical food-borne  infectious, typhoid  fever, epidemic  typhus, infectious  mononucleosis, pielitis, middle  otitis.

2.     Diseases  with  organic  damage  of  central  nervous  system, but  without  meningitis (brain  abscess, tetanus, subarachnoid  hemorrhage).

3.     Meningitis  of  other  etiology. In  purulent  meningitises  etiological  factors  may  be  pneumococci, staphylococci, streptococci, bacterium  coli, salmonella, fungi, Haemophilus  influenzae. In  purulent  meningitis  nonmeningococcal  etiology  it  is  necessary  to  reveal  primary  purulent  focus(pneumonia, purulent  processes  on  the  skin, otitis, sinusitis, osteomyelitis).

Treatment

http://www.ncbi.nlm.nih.gov/pubmed/12818909

The  therapeutic  tactics  depends  from  the  clinical  forms, severity  of  the  course  of  the  disease, presence  of  complications, premordal  state. In  serious  and  middle  serious  course  of  nasopharyngitis  antibacterial  remedies  are  used. Peroral  antibiotics oxacillin, ampyox, chloramphenicol, erythromycin  are  used.

The  duration  of  the  therapy  is  3-5 days  and  more. Sulfonamides  of  prolonged  action  are  used  in  usual  dosages. In  light  duration  of  nasopharyngitis  the  prescription  of  antibiotics  and  sulfonamides  is  no  obligatory.

In  therapy  of  generalized  forms  of  meningococcal  infection  the  central  place  is  occuped  by  antibiotics, in  which  salt  benzil penicillin stands  at  the  first  place. Benzyl penicillin  is  used  in  dosage  of  200,000-300,000 IU/kg/day. In  serious  form  of  meningococcal  infection  daily  dosage  may  be  increased  to  500,000 IU/kg/day. Such  doses  are  recommended  particularly  in  meningococcal  meningoencephalitis. In  presence  of  ependimatitis  or  in  signs  of  consolidation  of  the  puss  the  dose  of  penicillin increases  to  800 000 IU/kg/day.

In  similar  circumstances  it  is necessary  to  inject  sodium  salt  of  penicillin  by  intravenously  in  dose  2 000 000-12 000 000  units  in  day. Potassium  salt  of  penicillin  is  no  injected  by  intravenously, because  it  is  possible  the  development  of  hyperkalemia.  Intramuscular  dose  of  penicillin  is  preserved.  

Endolumbar  injection  of  penicillin  is  no  used  practically last years. Daily  dose  is  injected  to  the  patient  every  3  hours. In  some  cases  interval  between  injections  may  be  increased  up  to  4  hours. The  duration  of  the  therapy  by  penicillin  is  decided  individually  depending on  clinical  and  laboratory  data. The  duration  of penicicllin  therapy usually  5-8  days.

At  the  last  years  increased  resistant  strains  of  meningococcus  are  marked (till  5-35%). Besides  that, in  some  cases the  injection  of  massive  doses  of  penicillin  leads  to  unfavorable  consequences  and  complications (endotoxic  shock, hyperkalemia  due  to  using  of  potassium salt  of  penicillin, necroses  in  the  places  of  injections  and  other).  Also, the  patients  occur  with  allergy  to  penicillin  and  severe   reactions  in  anamnesis. In  such  cases   it  is  necessary  to  perform  etiotropic  therapy  with  use  other  antibiotics. In  meningococcal  infection  semisynthetic  penicillins  are  very  effective. These  remedies  are  more  dependable  and  preferable  for  “start-therapy”  of  the  patients  with  purulent  meningitis  till establishment  etiological  diagnosis. In  meningococcal  infection  ampicillin  is  the  best  medicine, which  is  prescribed  in  dosage  200-300 mg/kg/day  intramuscularly  every  4  hours.

In  the  most  serious  cases  the  part  of  ampicillin  is  given  intravenously. Daily  dose  is  increased  to  400 mg/kg/day. Oxacillin  is  used  in  dose  not  less  than  300 mg/kg/day  every  3  hours. Metycyllin  is  prescribed  in  dose – 200-300  mg/kg  every  4  hours. In  meningococcal  infection  chloramphenicol  is  highly effective. It  is  the  medicine  of  the  choice  in  fulminate  meningococcemia. It  is  shown, that  endotoxic  reactions  arise  more  rarely  during treatment  of  the  patients  by  chloramphenicol than  during  therapy  by  penicillin. In  cases  of  meningoencephalitis  chloramphenicol  is  not  prescribed  due  to  its  toxic  effects  on  neurons  of  brain. Chloramphenicol  is  used  in  dose  50-100 mg/kg  3-4  ties  a  day. In  fulminate  meningococcemia  it  is  given  intravenously  every  4  hours till  stabilization  of  arterial  pressure. Then chloramphenicol  is  injected  intramuscularly. The  duration  of  the  treatment  of  the  patients  by  this  antibiotic  is  6-10  days.

There  are  satisfactory  results  of  the  treatment  of  meningococcal  infection  by  remedies  from  the  group  of  tetracycline. Tetracycline  is injected  in  dose  25 mg/kg intramuscularly  and intravenously in  the  cases  of  resistant  agents  to  the  other  antibiotics.

Pathogenetic  therapy  has  exceptional  significance  in  therapeutic  measures. It  is  performed  simultaneously  with  etiotropic  therapy. The  basis  of  pathogenetic  therapy  is  the  struggle  with  toxicosis. Salt  solutions, macromolecular  colloid  solutions, plasma, albumin  are  used. Generally 50-40 ml of fluid is injected on 1 kg of body’s mass per day in adults under the control of diuresis. Prophylaxis  of  hyperhydratation  of  the brain  is  performed  simultaneously. Diuretics (lasix, uregit) are  injected. In  serious  cases  glucocorticosteroids  are  prescribed. Full  doses  is  determined  individually. It  depends  on  dynamics  of  the  main  symptoms  and  presence  of  complications. Generally  hydrocortisone  is  used  in  dose  of  3-7  mg/kg/day, prednisolone – 1-2 mg/kg/day. Oxygen  therapy  has  great  significance  in  the  treatment  of  the  patients

The  therapy  of  fulminate  meningococcemia  includs  the  struggle  with  shock. Adrenaline  and  adrenomimetics  are  not  used  due  to  possibility  of  capillary spasm, increased  hypoxia  of  the  brain  and  kidneys  and  development  of  acute  renal  failure. The  early  hemodialysis  is  recommended  in  the  case  of  acute  renal  failure  due  to  toxicosis.

The basis of the therapy of infectious-toxic shock is complex of measures, including application of antibiotics, improvement of blood circulation. The course of infectious-toxic shock is very serious, with high mortality (50 % of the patient die during the first 48 hours of the disease). Because, it is necessary to prescribe intensive therapy immediately. Antibiotics of wide spectrum of action are prescribed. Steroid hormones have important meaning in the treatment of infectious-toxic shock. Hormones decrease general reaction of the organism on toxin, positively act on hemodynamics. Treatment by glucocorticoids is conducted during 3-4 days.

When meningococcal disease is suspected, treatment must be started immediately and should not be delayed while waiting for investigations. Treatment in primary care usually involves prompt intramuscular administration of benzylpenicillin, and then an urgent transfer to hospital for further care. Once in hospital, the antibiotics of choice are usually IV broad spectrum 3rd generation cephalosporins, e.g. cefotaxime or ceftriaxone. Benzylpenicillin and chloramphenicol are also effective. Supportive measures include IV fluids, oxygen, inotropic support, e.g. dopamine or dobutamine and management of raised intracranial pressure. Steroid therapy may help in some adult patients, but is unlikely to affect long term outcomes.

Complications following meningococcal disease can be divided into early and late groups. Early complications include: raised intracranial pressure, disseminated intravascular coagulation, seizures, circulatory collapse and organ failure. Later complications are: deafness, blindness, lasting neurological deficits, reduced IQ, and gangrene leading to amputations.

 

Prophylaxis

http://www.nhstaysideadtc.scot.nhs.uk/TAPG%20html/Section%2016/menprophregime.htm

Prophylactic  measures, directional  on  the  sources  of  meningococcal  infection  include  early  revelation  of  the  patients,  sanation  of  meningococcal  carriers, isolation  and  treatment  of  the  patients. Medical  observation  is  established  in  the  focuses  of  the  infection  about  contact  persons  during  10  days.

The  measures against  of  the  transmissive  mechanism,  are  concluded  in  performance  of  sanitary  and  hygienic  measures  and  disinfection. It  is  necessary  to  liquidate  the  congestion, especially  in  the  closed  establishments (children’s  establishments, barracks’s  and  other). The  humid  cleaning  with  using  of  chlorcontaining  disinfectants, frequent  ventilation, ultra-violet  radiation  are  performed  at  the  lodgings.

 The  measures, directional  on  receptive  contingents, include  increase  nonspecific  resistance of  the  people  (tempering, timely  treatment  of  the  diseases  of respiratory  tract, tonsils) and  formation  of  specific  protection  from  meningococcal  infection. Active  immunization  is  more  perspective  with  help  of  meningococcal  vaccines. There are  several  vaccines, for  example, polysaccharide  vaccines  A  and  C.

Vaccine  from  meningococcus  of  the  group B  was  also  obtained. However, the group B capsular polysaccharide is not sufficiency immunogenic to produce a reliable antibody response in humans to be effective, several solutions to this problem are being studied, including the chemical alterations of the capsular B antigen to make it more immunogenic and the search for other cell wall antigens that  are  capable of eliciting bactericidal antibodies against B meningococci with a minimum of serious side effects. New vaccines against meningococcus are under development.