Meningeal syndrome iclinic of infectious diseases. Differential diagnosis of meningitis and meningoencephalitis. Diagnostic features of tuberculous meningoencephalitis. Edema-swelling of the brain. Differential diagnosis of nlesions of the oro-and nasopharynx, salivary glands (diphtheria, streptococcal pharyngitis/tonsillitis, nfuzospirohetous symbiosis, parotitis). Anaphylactic nshock and serum disease in clinic of ninfectious diseases

MENINGOCOCCAL INFECTION

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

Definition

 Meningococcal  infection  is  an  acute  infectious  disease  of  the  nhuman,  caused  by  meningococcous  Neisseria Meningitigis. The  nmechanism  of  the  transmission  of  the  infection  is  air-drop. The  ndisease  is  characterized     by  damage  of  mucous  membrane  of  nnasopharynx (nasopharingitis),  generalization   of  the  process in  form  of  nspecific  septicemia (meningococcemia) and  inflammation  of  the  soft  ncerebral membranes (meningitis).

Epidemiology

The importance of meningitis ndisease is as significant in Africa nas HIV, TB and malaria. Cases of meningococcemia leading to severe meningoencephalitis nare common among young children and the elderly. Deaths occurring in less tha24-hours are more likely during the disease epidemic seasons in Africa and nSub-Saharan Africa is hit by meningitis disease outbreaks throughout the nepidemic season. It may be that climate change contributes significantly the nspread of the disease in Benin, nBurkina 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 ndisease is endemic: meningitis is “silently” present, and there are always a few cases. When the number of cases npasses five per population of 100,000 in one week, teams are on alert. Epidemic nlevels are reached when there have been 100 cases per 100,000 populations over nseveral weeks.

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

The ndistribution of meningococcal meningitis in Africa

Pathogenesis

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

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

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

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

 Meningococci  penetrate  into  the  blood  after  break  of  nprotective  barriers  of  mucous  membrane  of  upper  respiratory  tract. nThere  is  hematogenous  dissemination (meningococcemia). It  is  accompanied  nby  massive  destruction  of  the  agents  with  liberation  of  endotoxin. nMeningococcemia  and  toxinemia  lead  to  damage  of  endothelium  of  the  nvessels. Hemorrhages  are  observed  in  mucous  membrane, skin  and  nparenchymatous  organs. It  may  be  septic  course  of  meningococcemia  with nformation of the secondary metastatic focuses in the endocardium, joints, ninternal mediums of the eyes.

In most of the ncases penetration of meningococci in the cerebrospinal fluid and the nsoft cerebral covering is fought about by hematogenous ways through the nhematoencephalic barrier. Sometimes meningococci may penetrate into the nskull through perineural, perilymphatic and the perivascular way of the nolfactory tract, through the enthoid bone.

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

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

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

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

 In  purulent  nmeningitis some  pathogenic  moments  are  promoted  by  rows  of  paradoxical  nappearances  in hematoencephalic  barrier  and  membranes  of  the  brain. In  nphysiological  conditions hematoencephalic  barrier  and  brain’s  membranes  ncreate  closed  space, preventing  brain’s  tissue  from  influence  of  nenvironment. In  this  case  secretion  and  resorbtion  of  cerebrospinal  nfluid  are  proportional. In  meningitis  closed  space  leads  to  increased  nintracranial  pressure  due  to  hypersecretion  of  cerebrospinal  fluid  and  nto  edema  of  the  brain. The  degree  of  swelling-edema  of  the  brain  is  ndecisive  factor  in  the  outcome  of  the  disease.

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

1.     nPenetration  nof  the  agent  through hematoencephalic  barrier, irritation  of  receptors  nof  soft  cerebral  membrane  of  the  brain  and  systems, forming  ncerebrospinal  fluid.

2.     nHypersecretion  nof  cerebrospinal  fluid.

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

4.     nSwelling-edema  nof  the  brain  hyperirritation  of  the brain’s  membranes  and  radices  of  ncerebrospinal  nerves.

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

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

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

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

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

The incidence of endemic nmeningococcal disease during the last 13 years ranges from 1 to 5 per 100,000 nin developed countries, and from 10 to 25 per 100,000 in developing countries. nDuring epidemics the incidence of meningococcal disease approaches 100 per n100,000. There are approximately 2,600 cases of bacterial meningitis per year nin the United States, and on average 333,000 cases in developing countries. The ncase fatality rate ranges between 10 and 20 per cent.

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

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

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

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

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

Morbid  anatomy

In meningococcal infection pathologoanatomical changes depend non form and duration of the disease.

Nasopharingitis is characterized by hyperemia of the pharyngeal walls, nedema of the epithelial cells, regional infiltration, hyperplasion and nhyperthophy of lymphoid follicles. Signs of catarrhic inflammation are found itrachea and bronchi.

Cases of fulminate meningococcal infection is characterized by blood nvessels disorders and severe impairments of blood circulation. The main target nare the microcirculation vessels. The vascular lumen turns narrow, thrombs are nfound. Thrombs  are usually found in small veins. Hemorrhages into skin, nsubcutaneous tissue, lungs, myocardium, subendocardial hemorrhages, hemorrhages ninto renal parenchyma, adrenals, brain and subarachnoidal space are typical.

 Hemorrhages ninto brain

 Purulent ninflammation

 

Meningococcous meningitis is characterized by serous or purulent ninflammation of pia mater.

 

Clinical manifestation

The incubation period is 1-10 days, more  frequently 5-7 days.

Classification of the clinical forms of meningococcal infection:

I. Primarily localized nforms:

a) meningococcal carrier state

b) acute nasopharyngitis;

c) pneumonia.

II. Gematogenously ngeneralized forms:

a) meningococcemia: typical acute meningococcal sepsis; chronic;

b) meningitis; meningoencephalitis;

c) mixed forms (meningococcemia + meningitis, meningoencephalitis).

d) rare forms (endocarditis, arthritis, iridocyclitis).

In meningococcal carriers  the clinical manifestations  are absent.

Meningococcal nasopharingitis

The most common complains of the a patients are headache, mainly in the nfrontal-parietal region, sore throat, dry cough, blocked nose, fatigue, nweakness, loss of appetite, violation  of  the  sleep. In most of the patients nbody temperature rises upto subfebrile and lasts for not more than 3-7 days, nsometimes 5-7 days. The skin is pale, conjunctival vessels and sclera are ninjected. There  are hyperemia and edema of  the mucous membrane of the nose. nIn many patients the posterior wall of the pharynx seem to be covered by mucous nor mucous – purulent exudation.

Inflammatory changes in the nasopharynx can be noticed after 5-7 days, nhyperplasion of lymphoid follicles lasts longer (till 14-16 days). In the nperipheral blood temperate leukocytosis with neutrophylosis and a shift of nleukocytaric formula to the left, increase in ERS  may  be revealed. nNasopharyngitis  precedes  to  development  of  generalized  forms  of  the  ndisease.

 

Meningitis

It  nmay  start  after  meningococcal  nasopharyngitis, but  sometimes  primary  nsymptoms  of  the  disease  arise  suddenly. In meningitis three  symptoms  are nrevealed constantly: fever, headache and vomiting. Temperature  is  increases  nquickly  with  chill  and  may  reach  40-41°C  during  few  hours. Intermittent, nremittent,  constant, double  waved  types  of  the  temperature  occur  in  nmeningitis. The patients  suffer  from  severe  headache, having  diffuse  or  npulsatory  character. Headache  is  very  intensive  at  the  night. It  increases  ndue  to  change  of  body  position, sharp  sounds, bright  light. Vomiting  narises  without  precedent  nausea. There  is  no  connection  with  food  and  nrelief  after  vomiting. It  is  rule  abundant, by “fountain”, repeated. nSometimes, vomiting  arises  on  the  peak  of  headache.

In  nmeningitis  hyperthermia, hyperkynesia, photophobia, hyperalgesia, hyperosmia  nare  noticed. These  symptoms  are  revealed  more  frequently  in  children. nThe  severe  convulsions  arise  in  the  many  patients  at  the  first  nhours  of  the  disease (clonic, tonic  or  mixed  types). In  small  children  nmeningococcal  meningitis  may  start  with  convulsions.

The  disorders  of  nconsciousness   occupy  the  great  place  in  clinical  picture (from  sopor  ntill  coma). The  loss  of consciousness  develops  after  psychomotoric  nexcitement. The  loss  of consciousness  at  the  first  hours  of  the  ndisease  is  unfavorable  sign.

During  objective  nexamination  meningeal  symptoms  stand  at  the  first  place. It  is  ndescribed  near  30  meningeal  signs. A  few  meningeal  signs  are  used  in  npractice: rigidity  of  occipital  muscles, Kernig’s  symptom, Brudzinsky’s  nsymptom (upper, middle  and  lower). The  estimate  of  state  of  fontanelle  is  nvery  important  in  infants. There  are  three  symptoms  of  meningitis  in  ninfant: swelling, tension  and  absence  of  fontanelles  pulsation.

There  is  no  accordance  nbetween  expression  of  meningeal  syndrome and  severity  of  the  disease. nThe  expression  of different  symptoms  is  no  similar  at  the  same  npatient. The  patient  has  compulsory  pose  during  serious  cases. He  lays  non  side  with  deflection  of  the  head  backwards. The  legs  are  curved  nin  knee-joint  and  pelvic-femoral  joint. The  legs  are  pulled  to  nabdomen. Asymmetry  and increased  tendinous, periostal  and  dermal  reflexes  nare   observed  in  the  patients. These  reflexes  may  be  decreased  during  nexpressive  intoxication. Pathological  reflexes  may  be revealed (such  as  nBabinski’s, Hordon’s,  Rossolimo’s  reflexes, foot’s clones), and  also  nsymptoms  of  damage  cranial  nervous  (more  frequently III, VI, VII, VIII  npairs).

 

 Patient’s specific pose in case of meningitis

The  nmultiple  symptoms  of the lesion of the  other  organs  and  systems  are  nconnected  with  intoxication. There  is  tachycardia  at  the  first  hours  nof  the  disease. Then  it  may  be  bradycardia. Arrhythmia, tachypnoea  n(30-40  times  in  minute)  are  possible. The  tongue  is  covered  by  dirty  nbrownish  coat. It  is  dry. Abdomen  is  pulled  inside. There  is  tension  nof abdomen muscles.

The  external  appearance   nof  the  patients  is  very  typical. There  is  hyperemia  of  the  face  and  nneck. Sclera’s  vessels  are  injected.

In  hemogram   high  nleukocytosis, neuthrophylosis  with  shift  of  formula  to  the  left, nincreased  ERS  are  observed. Small  proteinuria, microhematuria, ncylinderuria  are  marked  in  urine.

Fulminate  ncourse  of  meningitis

 With  syndrome  of  brain’s  swelling  nand  edema  is  the  most  unfavorable  variant. There  is  hypertoxicosis  nduring  this  form  and  high  percentage  of  mortality. The  main  symptoms  nare  consequence  of  inclination  of  the  brain  in  to  foramen  magnum  nand  strangulation  of  medulla  oblongata  by  tonsils  of cerebellum. nImmitant  symptoms  from  cardiovascular  and  respiratory  systems  develop  nquickly. Bradycardia  appears. Then  it  is  changed  by  tachycardia. nArterial  pressure  may  fall  catastrophically, but  it  increases  more  nfrequently  till  high  level. Tachypnoea  arises (till  40-60  times/min)  nwith  help  of  axillary  muscles. The  disorders  of   breath  lead  to  its  nsudden  interruption. These  symptoms develop in hyperthermia, clonic  cramps  nand  loss  of  consciousness. Cyanosis  of  the  skin, hyperemia  of  the  nface  are  marked. Pyramidal  signs,  sometimes  symptoms  of  damage  of  ncranial  nerves, decreased  corneal  reflexes  contraction  of  pupils  and  nits  decreased  reaction  on  light  are  determined. Death   occurs  due  to  nrespiratory  failure  at  the  first  hours  of  the  disease, rarely  on  2-3  nday  or  on  5-7  day.

Meningitis  nwith  syndrome  of  cerebral  hypotension

It  nis  rare  variant  of  the course  of  meningococcal  meningitis. It  is  nobserved  principally  in  children.

 The  disease  develops  nimpetuously, with  sharp  toxicosis  and  exicosis. Stupor  develops  quickly. nCramps  are  possible. Meningeal  signs  are  no  expressive,  because, the  ndiagnostics  is  difficult. Intracranial  pressure  rapidly  falls. In  this  ncase  the  volume  of  the  fluid  in  the  brain’s  ventricles  decreases. nVentricular  collapse  develops. In  infant  the  large  fontanelle  is  ndepressed. In  adults  and  children  supporting  moments  in  diagnostics  nare  clinical  signs  of  dehydration  and  hypotension  of  cerebrospinal  nfluid, which  flows  out  by  rare  drops. The  fall  of  intracranial  npressure  may  lead  to  development  of  severe  complication – subdural  nhematoma.

 

Meningitis  nwith  syndrome  of  ependimatitis (ventriculitis)

Now  nit  is  rare  form  of  meningitis. This  form  develops  during  late  or  ninsufficient  treatment  of  the  patients. Especial  severity  of  the  ndisease  is  connected  with  spread  of  inflammation  on  ventricles  nmembranes (ependime)  and  involvement  of  brain’s  substance  in  to  npathological  process.

The  principal  clinical  nsymptoms  are  total  and  expressive  muscular  rigidity. The  patients  naccept  the  particular  pose. The  disorder  of  psychic, sleeping,  tonic  nand  clonic  cramps  are  observed. The  body  temperature  is  normal  or  nsubfebrile  during  general  severe  state  of  the  patient. Vomiting  is  nconstant  symptom. Hydrocephalia  and  cachexia  develop due  to  prolonged  ncourse  and  (or)  noneffective  therapy  of  ependimatitis.

Meningoencephalitis

It  is  rare  form  of  meningococcal  infection. In  this  ncase  the  symptoms  of  encephalitis  predominate, but  meningeal  syndrome  nis  weakly  expressed. Meningococcal  encephalitis  is  characterized  by  nrapid  onset  and  impetuous  cramps, paresises  and  paralyses. Prognosis  is  nunfavorable. The  mortality  is  high  and  recovery  is  incomplete  even  in  nmodern  conditions.

Meningococcemia (meningococcal sepsis)

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

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

Exanthema  is  nmore  clear, constant  and  diagnostically  valuable  sign  of  nmeningococcemia.

 Exanthema nin case of meningococcemia

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

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

The  severe  development  of  the  rash  depends  from  the  character, nsize  and  depth  of  the  its  elements.  The  deep  and  extensive  nhemorrhages  may  be  necrosed. Then  it  may  be  formation  of  deep  ulcers. nSometimes  deep  necrosis  is  observed  on  the  limbs  and  also, necrosis  nof  the  ear, nose  and  fingers of  the  hands  and  legs.

 

5. nNecrosis of fingers

 Zones nof leg necrosis

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

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

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

 Secondary  nmetastatic  foci  of  the  infection  may  appear  rarely  in  the  vascular  nmembrane  of  the  eye, in  myocardium, endocardium, lungs  and  pleura. nSimilar  foci  arise  very  rarely  in  kidneys, liver, urinary  tract, borne  nmarrow.

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

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

Meningococcal sepsis is combined with meningitis in majority cases. In  n4-10 %  of  the  patients  meningococcemia  may  be  without  damage  of  the  nsoft  cerebral  covering. Frequency  of  meningococcal  sepsis  is  usually  nhigher  in  the  period  of  epidemic.

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

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

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

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

Mixed  nforms (meningococcemia + meningitis)

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

Rare forms of meningococcal infections

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

Diagnostics

The diagnosis of all forms of nmeningococcal infection is based on the complex of epidemiological and clinical ndata. The  final  diagnosis  is  established  with  help  of  the  laboratory  nexamination. Separate  methods have different diagnostical significance ivarious clinical forms of meningococcal infections.

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

In recognitioof generalized forms, anamnestical and clinical methods of diagnostics have nreal diagnostic significance, mainly in combination of meningococcemia and nmeningitis.

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

 Cerebrospinal  nfluid  in meningococcal meningitis

Pleocytosis  achieves till  10-30 10³  in  1  mcl. nNeuthrophils  leukocytes  predominate  in  cytogram. Neuthrophilous  compose  n60-100%  of  all  cells. In  microscopy  neuthrophils  cover  intirely  all  nfields  of  vision, inrarely. Quantity  of  protein  of  cerebrospinal  fluid nincreases  (till  0,66-3,0 g/l). There  is  positive  Nonne-Appelt’s  reaction. nThe  reaction  of  Pandy  composed (+++). Concentration  of  glucose  and  nchlorides  are  usually  decreased.

In  generalized forms  the  final  diagnosis  is  confirmed  by  nbacteriological  method. In  diagnostics  immunological  methods  are  used ntoo. Reactions of  hemagglutination, latex  agglutination  are  more  nsensitive.

 

Differential  diagnosis

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

It  is  nnecessary  to  differentiate  meningococcal  meningitis  with  extensive  ngroup  of  the  diseases:

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

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

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

Treatment

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

The  therapeutic  tactics  ndepends  from  the  clinical  forms, severity  of  the  course  of  the  disease, npresence  of  complications, premordal  state. In  serious  and  middle  nserious  course  of  nasopharyngitis  antibacterial  remedies  are  used. nPeroral  antibiotics oxacillin, ampyox, chloramphenicol, erythromycin  are  nused.

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

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

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

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

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

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

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

Pathogenetic  ntherapy  has  exceptional  significance  in  therapeutic  measures. It  is  nperformed  simultaneously  with  etiotropic  therapy. The  basis  of  npathogenetic  therapy  is  the  struggle  with  toxicosis. Salt  solutions, nmacromolecular  colloid  solutions, plasma, albumin  are  used. Generally 50-40 nml of fluid is injected on 1 kg of body’s mass per day in adults under the ncontrol of diuresis. Prophylaxis  of  hyperhydratation  of  the brain  is  nperformed  simultaneously. Diuretics (lasix, uregit) are  injected. In  nserious  cases  glucocorticosteroids  are  prescribed. Full  doses  is  ndetermined  individually. It  depends  on  dynamics  of  the  main  symptoms  nand  presence  of  complications. Generally  hydrocortisone  is  used  in  ndose  of  3-7  mg/kg/day, prednisolone – 1-2 mg/kg/day. Oxygen  therapy  has  ngreat  significance  in  the  treatment  of  the  patients

The  ntherapy  of  fulminate  meningococcemia  includs  the  struggle  with  shock. nAdrenaline  and  adrenomimetics  are  not  used  due  to  possibility  of  ncapillary spasm, increased  hypoxia  of  the  brain  and  kidneys  and  ndevelopment  of  acute  renal  failure. The  early  hemodialysis  is  nrecommended  in  the  case  of  acute  renal  failure  due  to  toxicosis.

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

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

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

Prophylaxis

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

Prophylactic  nmeasures, directional  on  the  sources  of  meningococcal  infection  include  nearly  revelation  of  the  patients,  sanation  of  meningococcal  carriers, nisolation  and  treatment  of  the  patients. Medical  observation  is  nestablished  in  the  focuses  of  the  infection  about  contact  persons  nduring  10  days.

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

 The  measures, directional  on  nreceptive  contingents, include  increase  nonspecific  resistance of  the  npeople  (tempering, timely  treatment  of  the  diseases  of respiratory  tract, ntonsils) and  formation  of  specific  protection  from  meningococcal  ninfection. Active  immunization  is  more  perspective  with  help  of  nmeningococcal  vaccines. There are  several  vaccines, for  example, npolysaccharide  vaccines  A  and  C.

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

Disease outbreak control

Meningitis A,C,Y and W-135 nvaccines can be used for large-scale vaccination programs when an outbreak of nmeningococcal disease occurs in Africa and other regions of the world. Whenever nsporadic or cluster cases or outbreaks of meningococcal disease occur in the nUS, chemoprophylaxis is the principal means of preventing secondary cases ihousehold and other close contacts of individuals with invasive disease. nMeningitis A,C,Y and W-135 vaccines rarely may be used as an adjunct to nchemoprophylaxis,1 but only in situations where there is an ongoing risk of nexposure (e.g., when cluster cases or outbreaks occur) and when a serogroup ncontained in the vaccine is involved.

It is important that nclinicians promptly report all cases of suspected or confirmed meningococcal ndisease to local public health authorities and that the serogroup of the nmeningococcal strain involved be identified. The effectiveness of mass nvaccination programs depends on early and accurate recognition of outbreaks. nWhen a suspected outbreak of meningococcal disease occurs, public health nauthorities will then determine whether mass vaccinations (with or without mass nchemoprophylaxis) is indicated and delineate the target population to be nvaccinated based on risk assessment.

MENINGITIS

Meningitis n(from Ancient Greek μῆνιγξ/méniŋks, n“membrane” and the medical suffix -itis, “inflammation”) is an acute inflammation of the nprotective membranes covering the brain nand spinal cord, knowcollectively as the meninges. nThe inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and nless commonly by certain drugs. nMeningitis can be life-threatening because of the inflammation’s proximity to nthe brain and spinal cord; therefore, the condition is classified as a medical emergency.

The most common symptoms of nmeningitis are headache and neck stiffness nassociated with fever, confusion or altered consciousness, nvomiting, and an inability to tolerate light (photophobia) or loud nnoises (phonophobia). Childreoften exhibit only nonspecific symptoms, such as irritability and drowsiness. If na rash is present, it nmay indicate a particular cause of meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied nby a characteristic rash.

A lumbar puncture ndiagnoses or excludes meningitis. A needle is inserted into the spinal canal to nextract a sample of cerebrospinal nfluid (CSF), that envelops the brain and spinal cord. The CSF is nexamined in a medical laboratory. The first treatment in acute meningitis nconsists of promptly administered antibiotics and nsometimes antiviral ndrugs. Corticosteroids ncan also be used to prevent complications from excessive inflammation. nMeningitis can lead to serious long-term consequences such as deafness, epilepsy, hydrocephalus and cognitive deficits, nespecially if not treated quickly. Some forms of meningitis (such as those nassociated with meningococci, Haemophilus influenzae type B, pneumococci or mumps virus infections) nmay be prevented by immunization. n

 

Meninges of the central nnervous system: dura mater, arachnoid, and pia mater.

Clinical nfeatures

Iadults, the most common symptom of meningitis is a severe headache, occurring ialmost 90% of cases of bacterial meningitis, followed by nuchal rigidity (the ninability to flex the neck forward passively due to increased neck muscle tone and nstiffness). The classic triad of diagnostic signs consists of nuchal rigidity, nsudden high fever, and naltered mental status; however, all three features are present in only 44–46% nof bacterial meningitis cases. If none of the three signs are present, nmeningitis is extremely unlikely. Other signs commonly associated with nmeningitis include photophobia n(intolerance to bright light) and phonophobia n(intolerance to loud noises). Small children often do not exhibit the naforementioned symptoms, and may only be irritable and look nunwell. The fontanelle (the soft nspot on the top of a baby’s head) can bulge in infants aged up to 6 months. Other features nthat distinguish meningitis from less severe illnesses in young children are nleg pain, cold extremities, and an abnormal skin color.

Nuchal rigidity occurs in 70% nof bacterial meningitis in adults. Other signs of meningism include the npresence of positive Kernig’s sign or Brudziński sign. nKernig’s sign is assessed with the nperson lying supine, nwith the hip and knee flexed to 90 degrees. In a person with a positive nKernig’s sign, pain limits passive nextension of the knee. A positive Brudzinski’s sign occurs when flexion of the nneck causes involuntary flexion of the knee and hip. Although Kernig’s sign and Brudzinski’s sign are both commonly used to nscreen for meningitis, the sensitivity of these tests is limited. They do, however, have nvery good specificity for meningitis: the signs rarely occur in other ndiseases. Another test, known as the “jolt accentuation maneuver” helps determine whether meningitis is npresent in those reporting fever and headache. A person is asked to rapidly nrotate the head horizontally; if this does not make the headache worse, nmeningitis is unlikely.

Meningitis caused by the nbacterium Neisseria meningitidis (known as “meningococcal meningitis”) can be differentiated from nmeningitis with other causes by a rapidly spreading petechial rash, which nmay precede other symptoms. The rash consists of numerous small, irregular npurple or red spots (“petechiae”) on the ntrunk, lower extremities, nmucous membranes, conjuctiva, and (occasionally) the palms of the hands or nsoles of the feet. The rash is typically non-blanching; the redness does not ndisappear when pressed with a finger or a glass tumbler. Although this rash is nnot necessarily present in meningococcal meningitis, it is relatively specific nfor the disease; it does, however, occasionally occur in meningitis due to nother bacteria. Other clues on the cause of meningitis may be the skin signs of nhand, foot and mouth disease and genital herpes, both nof which are associated with various forms of viral meningitis.

Meningitis is typically ncaused by an infection with microorganisms. Most ninfections are due to viruses, with bacteria, fungi, and protozoa being the nnext most common causes. It may also result from various non-infectious causes. nThe term aseptic nmeningitis refers to cases of meningitis in which no bacterial ninfection can be demonstrated. This type of meningitis is usually caused by nviruses but it may be due to bacterial infection that has already beepartially treated, when bacteria disappear from the meninges, or pathogens ninfect a space adjacent to the meninges (e.g. sinusitis). Endocarditis (ainfection of the heart nvalves which spreads small clusters of bacteria through the nbloodstream) may cause aseptic meningitis. Aseptic meningitis may also result nfrom infection with spirochetes, na type of bacteria that includes Treponema npallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease). nMeningitis may be encountered in cerebral malaria n(malaria infecting the brain) or amoebic nmeningitis, meningitis due to infection with amoebae such as Naegleria fowleri, ncontracted from freshwater sources.

Mechanism

The meninges comprise three nmembranes that, together with the cerebrospinal nfluid, enclose and protect the brain and spinal cord (the central nervous system). The pia mater is a very ndelicate impermeable membrane that firmly adheres to the surface of the brain, nfollowing all the minor contours. The arachnoid mater (so nnamed because of its spider-web-like appearance) is a loosely fitting sac otop of the pia mater. The subarachnoid nspace separates the arachnoid and pia mater membranes and is filled nwith cerebrospinal fluid. The outermost membrane, the dura mater, is a thick ndurable membrane, which is attached to both the arachnoid membrane and the skull.

In bacterial meningitis, nbacteria reach the meninges by one of two main routes: through the bloodstream nor through direct contact between the meninges and either the nasal cavity or nthe skin. In most cases, meningitis follows invasion of the bloodstream by norganisms that live upon mucous nsurfaces such as the nasal cavity. This is noften in turn preceded by viral infections, which break down the normal barrier nprovided by the mucous surfaces. Once bacteria have entered the bloodstream, nthey enter the subarachnoid nspace in places where the blood–braibarrier is vulnerable—such as the choroid plexus. nMeningitis occurs in 25% of newborns with bloodstream infections due to group B nstreptococci; this phenomenon is less common in adults. Direct contamination of nthe cerebrospinal fluid may arise from indwelling devices, skull fractures, or ninfections of the nasopharynx or the nasal sinuses that have formed a tract nwith the subarachnoid space (see above); occasionally, congenital ndefects of the dura nmater can be identified.

The large-scale inflammation that noccurs in the subarachnoid space during meningitis is not a direct result of nbacterial infection but can rather largely be attributed to the response of the nimmune system to the nentry of bacteria into the central nervous system. When components of the bacterial cell membrane are nidentified by the immune cells of the brain (astrocytes and microglia), they nrespond by releasing large amounts of cytokines, nhormone-like mediators that recruit other immune cells and stimulate other ntissues to participate in an immune response. The blood–brain barrier becomes nmore permeable, leading to (swelling of the brain due to fluid leakage from nblood vessels). Large numbers of white blood cells nenter the CSF, causing inflammation of the meninges and leading to “interstitial” edema (swelling due nto fluid between the cells). In addition, the walls of the blood vessels nthemselves become inflamed (cerebral vasculitis), which leads to decreased nblood flow and a third type of edema, “cytotoxic” edema. The three nforms of cerebral edema all lead to increased intracranial pressure; together with the lowered blood npressure often encountered in acute infection, this nmeans that it is harder for blood to enter the brain, consequently brain cells are ndeprived of oxygen and undergo apoptosis n(automated cell death).

It is recognized that administration of antibiotics nmay initially worsen the process outlined above, by increasing the amount of nbacterial cell membrane products released through the destruction of bacteria. nParticular treatments, such as the use of corticosteroids, are naimed at dampening the immune system’s response to this phenomenon.

Diagnosis

Blood tests and imaging

In someone suspected of nhaving meningitis, blood ntests are performed for markers of inflammation (e.g. C-reactive nprotein, complete blood count), as well as blood cultures.

The most important test iidentifying or ruling out meningitis is analysis of the cerebrospinal fluid nthrough lumbar npuncture (LP, spinal tap). However, lumbar puncture is ncontraindicated if there is a mass in the brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation. If nsomeone is at risk for either a mass or raised ICP (recent head injury, a knowimmune system problem, localizing neurological signs, or evidence oexamination of a raised ICP), a CT nor MRI scan is recommended prior to the lumbar puncture. This napplies in 45% of all adult cases. If a CT or MRI is required before LP, or if nLP proves difficult, professional guidelines suggest that antibiotics should be nadministered first to prevent delay in treatment, especially if this may be nlonger than 30 minutes. Often, CT or MRI scans are performed at a later nstage to assess for complications of meningitis.

In severe forms of nmeningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is commoin bacterial meningitis, due to a combination of factors, including ndehydration, the inappropriate excretion nof the antidiuretic hormone (SIADH), or overly aggressive intravenous nfluid administration.

n

CSF findings in different forms of meningitis
Type of meningitis	Glucose	Protein	Cells
Acute bacterial	low	high	PMNs, often > 300/mm³
Acute viral	normal	normal or high	mononuclear, < 300/mm³
Tuberculous	low	high	mononuclear and PMNs, < 300/mm³
Fungal	low	high	< 300/mm³
Malignant	low	high	usually mononuclear

Lumbar puncture

A lumbar puncture is done by npositioning the person, usually lying on the side, applying local anesthetic, and ninserting a needle into the dural sac n(a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this nhas been achieved, the “opening pressure” of the CSF is measured using a manometer. The npressure is normally between 6 and 18 cm water (cmH₂O); ibacterial meningitis the pressure is usually elevated. In cryptococcal meningitis, intracranial pressure is markedly nelevated. The initial appearance of the fluid may prove an indication of the nnature of the infection: cloudy CSF indicates higher levels of protein, white nand red blood cells and/or bacteria, and therefore may suggest bacterial nmeningitis.

The CSF sample is examined nfor presence and types of white blood cells, red blood cells, protein content and glucose level. Gram staining of the nsample may demonstrate bacteria in bacterial meningitis, but absence of nbacteria does not exclude bacterial meningitis as they are only seen in 60% of ncases; this figure is reduced by a further 20% if antibiotics were administered nbefore the sample was taken. Gram staining is also less reliable in particular ninfections such as listeriosis. nMicrobiological culture of the sample is more sensitive (it nidentifies the organism in 70–85% of cases) but results can take up to n48 hours to become available. The type of white blood cell predominantly npresent (see table) indicates whether meningitis is bacterial (usually nneutrophil-predominant) or viral (usually lymphocyte-predominant), although at nthe beginning of the disease this is not always a reliable indicator. Less ncommonly, eosinophils predominate, nsuggesting parasitic or fungal etiology, among others.

The concentration of glucose nin CSF is normally above 40% of that in blood. In bacterial meningitis it is ntypically lower; the CSF glucose level is therefore divided by the blood glucose (CSF nglucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial nmeningitis; in the newborn, glucose levels in CSF are normally higher, and a nratio below 0.6 (60%) is therefore considered abnormal.^[4] High levels nof lactate in CSF nindicate a higher likelihood of bacterial meningitis, as does a higher white nblood cell count. If lactate levels are less than 35 mg/dl and the persohas not previously received antibiotics then this may rule out bacterial nmeningitis.

Various other specialized ntests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused nby Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli nand group B streptococci; its routine use is not encouraged as nit rarely leads to changes in treatment, but it may be used if other tests are nnot diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by nGram-negative bacteria, but it is of limited use unless other tests have beeunhelpful. Polymerase chain reaction (PCR) is a technique used to amplify nsmall traces of bacterial DNA in order to detect the presence of bacterial or nviral DNA in cerebrospinal fluid; it is a highly sensitive and specific test nsince only trace amounts of the infecting agent’s DNA is required. It may identify nbacteria in bacterial meningitis and may assist in distinguishing the various ncauses of viral meningitis (enterovirus, nherpes simplex virus 2 and mumps in those not vaccinated for this). Serology n(identification of antibodies to viruses) may be useful in viral meningitis. If ntuberculous meningitis is suspected, the sample is processed for Ziehl-Neelsestain, which has a low sensitivity, and tuberculosis culture, which ntakes a long time to process; PCR is being used increasingly. Diagnosis of ncryptococcal meningitis can be made at low cost using an India ink stain of the nCSF; however, testing for cryptococcal antigen in blood or CSF is more nsensitive, particularly in people with AIDS.

A diagnostic and therapeutic difficulty is “partially treated meningitis”, where there are meningitis symptoms nafter receiving antibiotics (such as for presumptive sinusitis). When this nhappens, CSF findings may resemble those of viral meningitis, but antibiotic ntreatment may need to be continued until there is definitive positive evidence nof a viral cause (e.g. a positive enterovirus PCR).

Bacterial meningitis

The types of bacteria that cause nbacterial meningitis vary according to the infected individual’s age group.

• In premature babies and newborns up to three months old, common causes are group B streptococci (subtypes III which normally inhabit the vagina and are mainly a cause during the first week of life) and bacteria that normally inhabit the digestive tract such as Escherichia coli (carrying the K1 antigen). Listeria monocytogenes (serotype IVb) may affect the newborn and occurs in epidemics.
• Older children are more commonly affected by Neisseria meningitidis (meningococcus) and Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five by Haemophilus influenzae type B (i countries that do not offer vaccination).
• In adults, Neisseria meningitidis and Streptococcus pneumoniae together cause 80% of bacterial meningitis cases. Risk of infection with Listeria monocytogenes is increased in persons over 50 years old. The introduction of pneumococcal vaccine has lowered rates of pneumococcal meningitis in both children and adults.

n

Recent skull trauma potentially nallows nasal cavity bacteria to enter the meningeal space. Similarly, devices nin the brain and meninges, such as cerebral shunts, extraventricular drains or Ommaya reservoirs, ncarry an increased risk of meningitis. In these cases, the persons are more nlikely to be infected with Staphylococci, nPseudomonas, and other nGram-negative nbacteria. These pathogens are also associated with meningitis in people with an impaired immune system. nAn infection in the head and neck area, such as otitis media or mastoiditis, can lead nto meningitis in a small proportion of people. Recipients of cochlear implants for nhearing loss risk more a pneumococcal meningitis.

Tuberculous meningitis, which is meningitis caused by Mycobacterium tuberculosis, is more common in people from ncountries where tuberculosis nis endemic, but is also encountered in persons with immune problems, such as AIDS.

Recurrent bacterial nmeningitis may be caused by persisting anatomical defects, either congenital or nacquired, or by disorders of the immune system. nAnatomical defects allow continuity between the external environment and the nervous system. The nmost common cause of recurrent meningitis is a skull fracture, nparticularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids. nApproximately 59% of recurrent meningitis cases are due to such anatomical nabnormalities, 36% are due to immune deficiencies (such as complement deficiency, which predisposes especially to nrecurrent meningococcal meningitis), and 5% are due to ongoing infections iareas adjacent to the meninges.

 

VIRAL MENINGITIS

Viral meningitis refers to meningitis caused by a nviral infection. It is nsometimes referred to as aseptic nmeningitis in contrast to meningitis caused by bacteria.

An example is lymphocytic choriomeningitis.

Viral meningitis is most commonly caused by enteroviruses.^[2]

Causative organisms include:^[1]

• Enteroviruses
• Enterovirus 71
• Echovirus
• Poliovirus (PV1, PV2, PV3)
• Coxsackie A virus (CVA); also causes Hand foot and mouth disease
• Herpesviridae (HHV)
• Herpes simplex virus type 1 (HSV-1 / HHV-1) or type 2 (HSV-2 / HHV-2); also cause cold sores or genital herpes
• Varicella zoster (VZV / HHV-3); also causes chickenpox
• Epstein-Barr virus (EBV / HHV-4); also causes infectious mononucleosis/”mono”
• Cytomegalovirus (CMV / HHV-5)
• Human Immunodeficiency Virus (HIV); causes AIDS
• La Crosse virus
• Lymphocytic choriomeningitis virus (LCMV)
• Measles
• Mumps
• St. Louis Encephalitis virus
• West Nile virus

n

·         nFUNGAL MENINGITIS

There are a number of risk nfactors for fungal nmeningitis, including the use of immunosuppressants (such nas after organ transplantation), HIV/AIDS, and the loss nof immunity associated with aging. It is uncommon in those with a normal immune nsystem but has occurred with medication contamination. nSymptom onset is typically more gradual, with headaches and fever being present nfor at least a couple of weeks before diagnosis. The most common fungal nmeningitis is cryptococcal meningitis due to Cryptococcus neoformans. In Africa, cryptococcal nmeningitis is estimated to be the most common cause of meningitis  and it naccounts for 20–25% of AIDS-related deaths in Africa. Other common fungal nagents include Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Candida nspecies.

FUNGAL nMENINGITIS

There are a number of risk nfactors for fungal nmeningitis, including the use of immunosuppressants n(such as after organ transplantation), HIV/AIDS, and the loss nof immunity associated with aging. It is uncommon in those with a normal immune nsystem but has occurred with medication contamination. nSymptom onset is typically more gradual, with headaches and fever being present nfor at least a couple of weeks before diagnosis. The most common fungal nmeningitis is cryptococcal meningitis due to Cryptococcus neoformans. In Africa, cryptococcal nmeningitis is estimated to be the most common cause of meningitis and it naccounts for 20–25% of AIDS-related deaths in Africa.^[23] Other ncommon fungal agents include Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, and Candida nspecies.^[

PARASITIC nMENINGITIS

A parasitic cause is ofteassumed when there is a predominance of eosinophils (a type of white blood cell) in the CSF. The most ncommon parasites implicated are Angiostrongylus cantonensis, Gnathostoma spinigerum, Schistosoma, as nwell as the conditions cysticercosis, ntoxocariasis, baylisascariasis, paragonimiasis, and a nnumber of rarer infections and noninfective conditions.

NON-INFECTIOUS nMENINGITIS

Meningitis may occur as the nresult of several non-infectious causes: spread of cancer to the meninges (malignant or neoplastic meningitis) and certain drugs (mainly non-steroidal anti-inflammatory drugs, antibiotics and intravenous immunoglobulins). It may also be caused by several ninflammatory conditions, such as sarcoidosis (which is nthen called neurosarcoidosis), nconnective tissue disorders such as systemic lupus erythematosus, and certain forms of vasculitis n(inflammatory conditions of the blood vessel wall), such as Behçet’s disease. nEpidermoid cysts and dermoid cysts may ncause meningitis by releasing irritant matter into the subarachnoid space.^[3][16] Mollaret’s meningitis is a syndrome of recurring episodes of naseptic meningitis; it is thought to be caused by herpes simplex virus type 2. Rarely, migraine may cause nmeningitis, but this diagnosis is usually only made when other causes have beeeliminated.

Vaccination

Since the 1980s, many ncountries have included immunizatioagainst Haemophilus influenzae type B in their routine nchildhood vaccination schemes. This has practically eliminated this pathogen as na cause of meningitis in young children in those countries. In the countries nwhere the disease burden is highest, however, the vaccine is still too nexpensive. Similarly, immunization against mumps has led to a sharp fall in the nnumber of cases of mumps meningitis, which prior to vaccination occurred in 15% nof all cases of mumps.

Meningococcus vaccines exist against groups A, C, W135 and Y. nIn countries where the vaccine for meningococcus group C was introduced, cases ncaused by this pathogen have decreased substantially. A quadrivalent vaccine nnow exists, which combines all four vaccines. Immunization with the ACW135Y nvaccine against four strains is now a visa requirement for taking part in Hajj. Development of a vaccine against group B nmeningococci has proved much more difficult, as its surface proteins (which nwould normally be used to make a vaccine) only elicit a weak response from the immune system, nor cross-react with normal human proteins. Still, some countries (New Zealand, Cuba, Norway and Chile) have developed vaccines against local nstrains of group B meningococci; some have shown good results and are used ilocal immunization schedules. In Africa, until recently, the approach for nprevention and control of meningococcal epidemics was based on early detectioof the disease and emergency reactive mass vaccination of the at-risk npopulation with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines, nthough the introduction of MenAfriVac n(meningococcus group A vaccine) has demonstrated effectiveness in young people nand has been described as a model for product development partnerships iresource-limited settings.

Routine vaccination against Streptococcus npneumoniae with the pneumococcal conjugate vaccine (PCV), which is nactive against seven common serotypes of this pathogen, significantly reduces nthe incidence of pneumococcal meningitis. The npneumococcal polysaccharide vaccine, which ncovers 23 strains, is only administered to certain groups (e.g. those who have nhad a splenectomy, the nsurgical removal of the spleen); it does not elicit a significant immune nresponse in all recipients, e.g. small children. Childhood vaccination with Bacillus Calmette-Guérin has beereported to significantly reduce the rate of tuberculous meningitis, but its nwaning effectiveness in adulthood has prompted a search for a better vaccine.

Antibiotics

Short-term antibiotic nprophylaxis is another method of prevention, particularly of meningococcal nmeningitis. In cases of meningococcal meningitis, prophylactic treatment of nclose contacts with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) careduce their risk of contracting the condition, but does not protect against nfuture infections. Resistance to rifampicin has beeoted to increase after nuse, which has caused some to recommend considering other agents. While nantibiotics are frequently used in an attempt to prevent meningitis in those nwith a basilar skull fracture there is insufficient evidence to ndetermine whether this is beneficial or harmful. This applies to those with or nwithout a CSF leak.

DIPHTHERIA

http://www.medicinenet.com/diphtheria/article.htm

 

Diphtheria is an acute ninfectious disease caused by Leffler bacilli, transmitted mainly in aair-drop way and characterized by the symptoms of general intoxication, local ninflammation of the mucous membranes mainly with the formation of fibrinogenous nfur and typical complications on the part of the nervous system, cardiovascular system nand excretory system.

Diphtheria (Greek nδιφθέρα (diphthera) “pair of leather scrolls”) is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is ncharacterized by sore throat, low fever, nand an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal ncavity. A milder form of diphtheria can be restricted to the skin. Less commoconsequences include myocarditis n(about 20% of cases) and peripheral neuropathy (about 10% of cases).

Diphtheria is an infectious ndisease spread by direct physical contact or breathing the aerosolized secretions nof infected individuals. Historically quite common, diphtheria has largely beeeradicated in industrialized nations through widespread vaccination. In the United States, for nexample, there were 53 reported cases of diphtheria between 1980 and 2000, but nonly a total of 2 cases of diphtheria have been reported in the 21st century, nthe last of which was in 2003. The diphtheria–pertussis–tetanus (DPT) vaccine is nrecommended for all school-age children in the U.S., and boosters of the nvaccine are recommended for adults, since the benefits of the vaccine decrease nwith age without constant re-exposure; they are particularly recommended for nthose traveling to areas where the disease has not been eradicated.

Epidemiology

Diphtheria is fatal ibetween 5% and 10% of cases. In children under five years and adults over 40 nyears, the fatality rate may be as much as 20%. As of 2010 it caused about n2,900 deaths down from 6,300 in 1990.

Outbreaks, though very rare, nstill occur worldwide, including in developed nations, such as Germany and Canada. After the breakup of the nformer Soviet Union in the nlate 1980s, vaccination rates in its constituent countries fell so low that nthere was an explosion of diphtheria cases. In 1991, there were 2,000 cases of ndiphtheria in the USSR. By 1998, according to Red Cross estimates, nthere were as many as 200,000 cases in the Commonwealth of Independent States, with 5,000 ndeaths.^[14] This was so ngreat an increase that diphtheria was cited in the Guinness Book of World Records as “most resurgent disease”.

Disability-adjusted life year for diphtheria per n100,000 inhabitants in 2004

Pathogenesis

The diphtheria infection develops only in case of the parenteral entering nof poison into the organism. Implanting in the organism through covering ntissues the diphtheria pathogens form local foci of histic damage. More ofteit happens on the mucous membranes of the stomatopharynx, nasal-courses where nthe microbes utilize slime as a medium, less often the foci develop on the skiand even less often on the mucous membranes of an eye and vulva-vaginal area. nAlongside with classic exotoxin, which is a true lethal factor, the diphtheria nmicrobes in the zone of inoculation produce numerous solvable local-acting nfactors (hyaluronidase and neuraminidase) damaging the cells and facilitating nthe diffusion of bacteria and toxins in the tissues.

That is why nthe damage of almost all tissues is observed in the inoculation zone including nthe mucous membranes, skin, muscles, and nervous fulcrums. Hyperemia, nretardation of the blood flowand sharp rising of the permeability of nhysto-hematic barriers promote the formation of exudate which is rich in proteiand fibrinous membranes in the damaged tissue area.

At the nintranevral injection the diphtheria toxin causes the primary lesion of noligodendrocytes (Shvann cells) and myelin with the subsequent development of nthe sectional demyelination in area of inoculation. As a result the speed of PA ndecreases, the retractor periods are  prolonged, but the full passing block ndoes not appear.

The local cytopathogenic effect of the toxin is determined by the rate of nthe poison entering the tissues, by the toxin-aggregating capacity of the cells nand the availability of the microbial spreading factors (neuraminidase, nhyaluronidase). If poison enters slowly, there appear conditions for the nmanifestation of its local cytotoxic action in the area of inoculation, but if nthe toxin concentration in this area increases rapidly, then in a short time nthe “threshold” dose is accumulated, and in case of its exceeding the poison is nreabsorbed in the circulation system and already has a predominantly systemic npathogenic effect.

In the blood nthe toxin contacts with globulins, and at a greater saturation with albumines. nThe poison forms complexes with hemolysins and hemagglutinins.

The process of nthe poison fixation in tissues is not accompanied by any disorders of proteins, ncarbohydrates and fat metabolism. After the completion of the latent stage and nthe development of the characteristic symptoms of toxic diphtheria the patients nhave only a mild increase of the sugar content in the  blood without changing nthe tolerance to galactose and levulose.

There is nnoticeable weakening of phosphorylation processes in toxic diphtheria. The nchanges of oxidative phosphorylation in mitochondrions are not the result of nthe toxin direct pathogenic action, but the indirect one through the nneurohumoral part including the sympaticoadrenal system.

Clinical manifestations

The incubation period, as in the other forms of diphtheria, lasts from 3 nto 10 days. The disease has either an acute, sudden, or step-by-step oncoming nwith hardly noticeable symptoms, in the first case the temperature immediately nrises up to 38-39 °C, there is a headache, malaise. In the second case a child ndevelops poor appetite, flaccidity, slight temperature rise (37.5-38 °C) during several days. Quite often even senior children do not complain of a sore throat or the npain is insignificant, and if the doctor is not in the habit of examining a nthroat in each patient with a fever, diphtheria in such cases is not revealed nby the parents and the doctor as well. If the patient is examined during the nfirst day of the disease it is possible to notice a slight pulse acceleration, nwhich correlates with the temperature; the cervical glands are usually slightly nenlarged on one side, painful at pressing. The tongue is furred, the tonsils nare swollen either both or mostly, one of them, turn red, but the erythema is nstrictly localized and does not spread on the uvula and soft palate as iscarlatina. It is possible to discover fur on the reddened tonsil, during the nfirst hours of the disease it looks like a mild combustion of the mucous nmembrane or a heavy-bodied web grid; it is possible even to remove it by a ncotton plug but a new one appears on its place extremely fast, and it cannot be nremoved any more. By the end of the first day or by the beginning of the second nday the fur gets a characteristic diphtheria cover properties: it is dirty-gray nor yellowish, rather thick, rises above the mucous membrane surface, it cannot nbe removed without bleeding; plenty of fibrin and diphtheria bacilli can be ndiscovered under the microscope in it. The manifestations of the general nintoxication remain insignificant: a headache, malaise, poor appetite. The nborders of the heart are normal and the tones are clean. The pulse is naccelerated; the blood pressure is in  the normal range or slightly heightened. nThe liver and spleen are not changed; the urine does not contain protein. There nis moderate leukocytosis (10,000-12,000) and neuthrophylia in the blood. The following ncourse of the disease can be diverse. Nowadays, when the serum treatment is nwidely applied, the natural course of diphtheria can be observed very seldom. nTherefore, it is necessary to distinguish the diphtheria course during serum ntreatment and without it.

If serum is ninjected, sometimes within the first day there is no essential change in the npatient’s condition: the temperature remains elevated, the general condition is nalso abnormal, fur can even increase. But as a rule, there is a sharp improvement nin 24 hours: the temperature critically drops, sometimes down to normal, the nchild becomes vigorous and cheerful, the appetite improves, the cervical nglands-get smaller, the fur changes its appearance: it becomes more porous, it nlooks as if it is uplifted above the mucous membrane, there is a girdle of nsharply expressed erythema on the edges, the diffusion of the fur, is nintercepted. Within the following day and night the considerable part of the nfur disappears, in 2-3 days the fauces completely refine, and the child nrecovers. If serum is injected in time, the consequences of the intoxicatio(paralyses, heart weakness) don’t usually develop.

There are also cases when the temperature drops on the 3-5-th day and the nfur also disappears rather fast without any serum treatment. But such cases are nan exception. In most cases the disease progresses, the fur covers both ntonsils, it can spread to the uvula and aerofoil; the cervical glands are nenlarged, painful, but there is no edema of the cervical cellular tissue and nfauces. There are sometimes traces of protein in urine. The temperature is of nthe remittent (febris remittens) or improper type and lasts during 7-12 ndays. The fur disappears slowly without any ulcerations or detects of the nmucous membrane. The disease ends on the 7-15th day; the isolated paralyses n(paralysis of the soft palate) and unexpressed cardiac disorders are sometimes nobserved.

Ithe cases when the disease is not treated with serum, it is impossible to be nsure in the complete recovery of the patient even if the process stops and the nfur disappears. The fur sometimes appears again and can spread to the nnasopharynx and nasal cavity or the process goes downwards to the larynx.

 

Diphtheria of the fauces and diphtheria of the nnose

The transfer of the process from the tonsils to the nasal cavity is nimplemented either directly or skipping the soft palate and pharynx, the nprocess affects the nasopharynx  and rear parts of the nose. Such transfer is nusually observed not earlier than on the 3-5-th day of the disease and is naccompanied by a new temperature rise and deterioration of the general ncondition, and there are characteristic symptoms indicating the affection of nthe nasopharynxes and nasal cavity. The voice becomes nasal, the mouth is open, nthe tongue is dry and coated with peels, a slimy at first and then sanious ndischarge comes out of the nose, and frets the skin ‘around the nostrils and othe lips. An abundant purulent discharge can also be seen on the rear wall of nthe pharynx. Not only the submandibular lymphatic glands, but also the nlymphatic glands situated around m. sterno-cleido-mastoideus nswell up a little on-the neck. If the process has gone far and has affected the nforefronts of the nose, it is possible to see the covers without any ninstruments having cleared the nose entrance from purulent discharge and peels. nThe spreading of diphtheria on the nose worsens the prediction, as sometimes aedema of the cervical cellular and the symptoms of general intoxicatioaccompany it, i.e. the widespread diphtheria changes into toxic one. In other ncases the process can proceed to the nasal sinuses and middle ear. Clinically nthis transfer can remain unnoticed or corresponding symptoms may appear (edema nof blepharous and the back of the nose, discharge form the ears). Whether this ntransfer is caused by the diphtheria infection itself or a mixed infectioplays some role (streptococcus, pneumococcus), — it is not always possible to nfind out (the information on primary diphtheria of the nose can be found nbelow).

 

Diphtheria of the fauces and diphtheria of the nmouth

If the process spreads to nthe oral cavity, dirty-gray densely sitting covers develop on the palate, othe mucous membrane of the lips and cheeks, and also on the tongue. The bacteriological nresearch discovers Leffler’s bacilli in the covers.

The clinical symptoms: abundant salivation, smell from the mouth, painful nmastication and swallowing, large swelling of submandibular glands. The covers ndisappear slowly leaving the ulcers that do not heal for a long time.

 

 

 

 

 

 Diphtheria nof the oral cavity

Aadherent, dense, grey pseudomembrane covering the tonsils is classically seein diphtheria

The diphtheric affection of the larynx and respiratory tracts is knowunder the name of a croup.

Croup (true, diphtheric) can be secondary, if it develops after the naffection of the fauces or the nose, and primary – at the primary localizatioof the diphtheria process in the larynx.

 

The course of croup can be divided into three stages.

1. A ncroup cough stage. The first symptom indicating the starting affection of the nlarynxes is sharp loud cough, which becomes rasping, barking very soon. Senior nchildren complain of the sense of smart and pressure in the larynx; the npalpation of the larynx appears to be painful. At the same time the voice nbecomes hoarse, unclean, and then completely silent (aphonia). At the nexamination with a laryngeal mirror it is often possible to see an edema and nhyperemia of the epiglottis, and often there are no covers at this stage. This nperiod lasts 1-2-3 days and develops into a second stage.

2. A stenosis stage. The nrespiration becomes labored, unclean; at each inspiration the sawing or nwhistling sound is audible. This sound is weak at the beginning and audible nonly during exaltation and the child’s cry, then it becomes sharp, constant and nis audible from the distance. Another symptom is the larynx narrowing — nretraction of compliant, weaker places of the thoraces. As the insufficient namount of air enters the lungs through the narrowed glottis, the intrapulmonic npressure becomes lower than the atmospheric one and under its influence- the ncompliant places of the thoraces — the supraclavicular and bulbar-fossas; nintercostal spaces, anticardium – are more or less sharply retracted at each ninhalation. At first a child is quiet, satisfactorily manages the air ndeficiency. Then the oxygen deficiency develops – the child becomes restless, nrushes in bed, jumps up, grasps the handles of the bed, wants to be held in his nmother’s arms, showers his head to the back. The auxiliary muscles start to nwork – intercostal, mm. sterno-cleido-mastoidei, mm. scaleni. The nsterno-clavicular muscle appears to be noticeably tight at the palpation during nan inhalation. When the child is in such a condition, injecting the serum and  nproviding the adequate treatment (an operation and other treatment measures; n(see Treatment of croup below) can save him. If the disease has its natural ncourse, the condition improves and the stenosis easies in the extremely ninfrequent cases when the cover disappears; in most cases the disease reaches nits last stage.

3. An asphyxia stage. In the struggle with stenosis the child exhausts, nthe respiratory muscles get tired. The child becomes calm, sleepy, he ninditfferently lies in bed. The respiration is accelerated, but it is nsuperficial, the retractions are already not so visible. The lips, tip of the nnose and nails become blue, the face turns pale, sweat quite often appears on the nforehead. The extremities are cold, the pulse is very rapid, thready, sometimes nparadoxical (abasement of the pulse wave during the inhalation). From time to ntime there are attacks of acute dyspnea – the child jumps up, rushes because of nair-deficiency, the eyes express fright, the face becomes cyanotic; sometimes nsuch attacks result in the immediate death; in other cases the child dies after na more or less continuous agony with the symptoms of exhaustion of respiratory nand circulation centers.

Toxic diphtheria

The typical form sometimes develops on the 3-5th day of the disease from nthe localized form when the process affects the nasopharynx and oral cavity, nmore often it develops as it is from the very beginning. In this case the ndisease has an acute oncoming, which is more rapid than in localized ndiphtheria. The temperature immediately rises up to 39-40 °C, there is a headache, repeated vomiting, sometimes abdominal pains. Senior children complain of na pain at swallowing. The pulse is rapid: 140-160 beats per minute, the face is npale, there is malaise, sleeplessness, sometimes exaltation. The submandibular nglands are enlarged, painful; it is possible to see a quaggy pasty edema of the ncellular under the low jaw angle, usually on one side (Fig. 5) sometimes aedema develops only on the second day.

At the mouth nexamination you can see that the tongue is dry and furry, the fauces are ndark-red and hydropic; there is usually dirty-gray fur on one tonsil, it ncannot  be removed by a cotton plug. This fur affects the entire tonsil, passes nto the uvula, sometimes to the soft palate extremely fast, within several nhours. On the second or third day the disease is in full swing, and it is not ndifficult to clinically diagnose toxic diphtheria. The temperature remains high: n39-40 °C. The face is pale, pathy. There is sanious fluid discharge from the nnose, it frets the skin. The mouth is open, the lips are dry and cracked; the nsmell can sometimes be sensed even from the distance. The respiration is nhoarse, the voice is muffled, with a strong nasal tone. The glands are enlarged neven more, but it is more difficult to palpate them because the edema of the nfat cellular takes a considerable part of the neck. The glands are not so tight nbecause of the edema of the cellular, as compared with scarlatina. Thick, ndirty-gray covers are not only on the tonsils and uvula, but also on the mild nand firm palate; the edema of the whole fauces is considerably expressed; the nuvula is especially edemic and enlarged; it is squeezed and strangulated by the nenlarged tonsils, sometimes it is twisted backwards, so that the back wall of nthe pharynx is not visible. As a result of such swelling of the fauces the nrespiration becomes labored, stenotic (stenosis of the pharynx). The swallowing nis extremely painful, and the feeding of the patient becomes difficult. nSimultaneously with worsening of the local process the phenomena of the general nintoxication also increase: the pulse is rapid and weak, the heart sounds are ndummy, the blood pressure is low; there is protein in urine, sometimes ncylinders; general malaise is considerably expressed. There is considerable nleukocytosis in the blood (up to-15-20 thousand) and neutrophilia.

 

Complications

The most frequent diphtheria complication for adults is myocarditis. The naffection of the heart is especially typical for the toxic forms of the ndisease.

The severe form of myocarditis develops only in the patients with toxic ndiphtheria (except subtoxic) at overdue (after the 5th day of the disease) nspecific treatment and is always accompanied by complications on the side of nthe kidneys and nervous system.

The complications caused by the affection of the nervous system are nobserved less frequently. In the mild forms of diphtheria (localized, nwide-spread) the adults develop only the soft palate paresis — mononeuritis, nwhich has an easy short-term course (no more than 10-14 days), characterized by na snuffling voice and chokes while eating liquid food. In more than 1/3 cases ntoxic diphtheria is complicated by polyneuritis in various combinations and npolyradiculoneuritis. Among the cranial nerves the IX, X, III, VII, XII pairs nare affected more often, it results in paresis or paralyses of the soft palate, npharynx, tongue, accommodation paresis and mimicry affection.

 The severe forms of polyradiculoneuritis develop only in patients with nconcomitant alcoholism, they are characterized by deep wide-spread paralyses of nthe extremities, body, neck, respiratory muscles in combination with the naffection of the cranial nerves, resulting not only in the long-lived disorders nof the working capacity, but also in lethal outcomes, even in subtoxic ndiphtheria.

One or two-sided focal pneumonia quite often develops at the early stage nof the disease in toxic diphtheria.

 

Diagnosis

The modern microbiologic diagnosis of diphtheria is based on the cleaculture isolation and identification of the pathogen by the ncultural-morphological, biochemical and toxicogenic properties. Thus, it is nnecessary to strictly observe a number of conditions. The slime from the nstomatopharynx and nose as well as the secret from other areas of the npathological process localization are collected by separate wads before eating nor after it but not earlier than in 2 hours, and also before gargling and other nkinds of treatment (drops, ointments, wads).

Taking the material for research correctly is of great importance. In the nstomatopharynx slime is taken from the tonsils, palatal aerofoils, uvula and ntrailing wall of the pharynx by rotary movements of a wad obligatory with the nhelp of a glass spreading rod, not touching the mucous membrane of the cheeks nand tongue. If there is fur of fibrinous nature, the material should be takeboth from the affected tissues and the healthy tissues adjacent to them. A nsmall part of the removed coat, which is carefully ground between glasses, or a nsmear taken by a separate wad are sent to the laboratory for the direct nbacterioscopic investigation. The scooping of the material from the nose should nbe done after the careful preliminary purification of it from the slime by a ndry cotton plug or after blowing the nose.

Though the nstreamlining of some stages of the bacteriological research accelerates the nterms of carrying out an analysis to some extent, they all remain rather nprolonged and do not guarantee the early diagnostics of diphtheria.

Serological, immune-chemical and the immunological methods play a more nand more relevant role in the diagnostics and epidemiological evaluation of the ndisease. On their basis are designed the accelerated methods of discovering ndiphtheria toxin in clean and blended cultures in case of growing them iliquid mediums and other substrates.

The serological tests are applied to nstudy collective immunodeficiency. RDGA is the most accessible, simple and quite ninformative.

 

Differential diagnosis

The diagnosis of diphtheria of any localization is quite difficult, as it nis similar to many diseases of the infectious and non-infectious origin. The nnumber of diagnostic mistakes increased in the period of diphtheria nelimination, at a sporadic case rate, as the vigilance towards this infectiovanished. The mistakes are the most frequent in diagnosing diphtheria of the nstomatopharynx — the most widely spread form of the disease.

The localized nform of diphtheria of the stomatopharynx is the most difficult for the clinical ndiagnostics. The disease should be suspected if there is dense and nitidous fur nsituated on the domed surface of the tonsils, their swelling, which corresponds nto the area of the fur, limited hyperemia of the mucous membrane in the form of na thin rim with a cyanotic shade. The diffuse bright hyperemia, which affects nall the departments of the stomatopharynx, is not characteristic of localized ndiphtheria. While observing the patients it is possible to notice other nsymptoms, which help to diagnose the case. So, such symptoms as a short-living n(1-3 days) fever, the absence of pain at swallowing in 2-3 days with the nremaining fur are characteristic of localized diphtheria of the stomatopharynx.

It is necessary nto remember that in the patients suffering from chronic tonsillitis the nsymptoms of diphtheria may be distorted. In such patients the fever remains nlong, the fur is situated in the hypertrophied tonsils lacunas, and the nhyperemia of the mucous membrane is of a diffuse nature. If there are no nconvincing symptoms of angina in the patient who is in the diphtheria focus, it nis necessary to diagnose diphtheria even if there is no bacteriological nconfirmation of the diagnosis.

In comparisowith other diseases, localized diphtheria of the stomatopharynxes should be ndifferentiated from follicular and lacunar angina of the streptococcal nand staphylococcal etiology more, frequently. The considerable nintoxication (malaise, weakness, joint aches, headache) is characteristic of nthese diseases even if there is slight fur on the tonsils. The fur that is nlocated on the lacunas and has a quaggy, viscid consistence, yellow or nvirescent color is different too. The fur is localized or solid, usually dull nand can be easily removed by a glass spreading rod. The hyperemia of the mucous nmembrane is more often bright and diffuse. The appearance of the patient is nalso different: palenesses characteristic of diphtheria, but feverish blush, nshine in the eyes, brightness and dryness of the lips are characteristic of nangina.

Ulcerus-necrotic nangina of Simanovsky-Vincent’s is quite often taken for diphtheria, and vice versa. nThe peculiarity of this angina is the absence or minor expressiveness of nintoxication. The temperature is subfebrile or normal, the pain at swallowing nis slight. As a rule, the process is one-sided. On the tonsil develops the nulceration in the shape of a crater, coated by clotted fur of the virescent ncolor. The areas of necrosis can also be found on the palatal airfoil, uvula or nsoft palate.

The nanginous form of tularemia looks like diphtheria by the form of the fur on the tonsils, nbut it differs by a rather late development (on the 3-5th day), absence of aedema of the tonsil, the ulcer-necrotic-nature of a lesion (the fur not only nrises above the level of the healthy tissue, but is also located below it), a nconsiderable increase of the regional lymph nodes that continue enlarging after nthe disappearance of tonsillitis.

Necrotic nangina in scarlet fever can be considered to be diphtheria owing to the vastness of nthe lesion areas and dense fur cohesion with die tonsils surface. However, ithis case the affected areas of the tonsils do not rise above the level of the nhealthy tissue, the edema of the mucous membrane is insignificant, the nhyperemia is extremely bright and at the same time has a distinct border. It is nalso necessary to take into consideration the patient’s appearance: bright nhyperemia of the cheeks and paleness of the nosolabial triangle. The ndevelopment of the small-dot rash in the typical places for scarlatina solves nthe problem of the diagnosis.

Widespread diphtheria of the nstomatopharynx is diagnosed easier than localized one: the spreading of the fur from nthe tonsils on the adjacent parts of the stomatopharynx — palatal aerofoils, nuvula — indicates that the process is not ordinary. The edema of the mucous nmembrane testifies in favor of diphtheria. While diagnosing widespread ndiphtheria, it is necessary to be convinced of the absence of the hypodermic cellular nedema of the neck not to fail to diagnose toxic diphtheria.

Toxic ndiphtheria of the stomatopharynx is characterized by in especially bright clinical npicture, nevertheless, the greatest number of mistakes is made in both childreand adults in this case. Apparently, the main cause of  it lies in the fact nthat toxic diphtheria is a comparatively rare disease and the doctor lacks npersonal observations, which could help him to diagnose the disease. The maisymptoms of the early period of toxic diphtheria are an edema of the nneck-hypodermic, cellular, an edema of the stomatopharynx mucous membrane and nwidespread fur on it.

Contagious nmononucleosis should sometimes be differentiated from toxic diphtheria. The nresemblance is explained by the fur on the tonsils that has irregular depth nirregular consistence of the neck hypodermic cellular above the enlarged lymph nnodes. In contrast to toxic diphtheria contagious mononucleosis develops nstep-by-step, the quaggy fur on the tonsils occurs not earlier than on the 3-4-th nday, it can be rather easily removed by a glass spreading rod and is ntriturated. A long-lived fever, polyadenitis with primary enlargement of the nposterior neck lymph nodes, hepatolienal set of symptoms and characteristic npattern of the peripheral blood, in which one the uninuclear cells dominates, — ntestify in favor of contagious mononucleosis.

Treatment

http://www.mayoclinic.com/health/diphtheria/DS00495/DSECTION=treatments-and-drugs

 Hospitalization of patients is obligatory. In case of a  toxic ndiphtheria  patients transport only laying. The severe confinement bed regime nis necessary during 20-25 days, then at absence of complications the patient nallow to sit and gradually dilate impellent regime. At mild forms (localized ndiphtheria of pharynx,  diphtheria of nose) duration of confinement bed regime nis reduced up to 5-7 days. In the acute period of disease fluid and semifluid nnutrition is necessary. Treatment may be specific and pathogenic.

Specific treatment will carry out by high purified horse hyper immune nserum. For prevention of anaphylactic reactions infuse serum behind by Bezredko nmethod. First of all 0,1 mL diluted 1 : 100 of serum infuse intracutaneous of nforearm. If after 20-30 min. on a place of injection there are not changes or nthe papule in diameter is not more than 0,9 sm, – reaction is negative, and ninfuse 1 mL undiluted Serum sub dermal, and at absence of reaction – after 30 nmin all prescript dose in muscle.

At toxic diphtheria II-III stage and the hyper toxic form a serotherapy nis carried out necessarily, under protection of hormonal preparations, and nsometimes – narcosis. In case of positive intradermal assay or at presence of nanaphylactic reactions further subdermal infusion of serum only behind nunconditional indications. Serum in dilution 1: 100 is infused in a sub dermal nfat of brachium in doses 0,5; 2; 5 mL consecutive with intervals 20 min. At nabsence of reaction to previous dose infuse 0,1 mL undiluted serum nsubcutaneously. If reaction is not present, through 30 min infuse all nprescribed dose subcutaneously. In unusual cases serum is infused under nnarcosis.

Antitoxic serum nneutralizes only a toxin, which circulates in a blood, and does not influence non fixed in tissues. Therefore specific treatment may be carried out as soon as npossible (optimum in 1 – 3 rd day of disease).

The form of diphtheria ndetermines doses of serum for the first introduction and course of treatment.

At late (after 2 nd day of ndisease) beginning of treatment of patients with the widespread or toxic form nthe first dose of serum should be increased. The form of disease also ndetermines frequency rate of infusion of serum. In case of localized diphtheria nof a throat, nose, rare localization of process and early serotherapy is npossible to be limited by disposable infusion of serum. If diphtheria of throat nis widespread, infuse Serum during 2-3 days (at the toxic form – through every n12 hours). The first dose makes 1/3 – 1/2 course; in first two days patient may nreceive ¾ of course doses.

In case of diphtheritic ncroup the initial dose of Serum is determined by it’s stages – 15-20 thousand nAUN, II stage – 30-40 thousand AUN ,  at III stage- 40 thousand AUN, through 24 nhours this dose repeat, and the following one of these days if it is necessary, ninfuse half dose of Serum.

Usually the course of nserotherapy lasts no more than 3-4 days. Indications for stopping of nserotherapy are disappearance or decreasing of spot, edema of pharynx and nhypodermic fat of the neck, at croup – complete disappearance or decrease of nstenotic respiration. At suspicion on toxic diphtheria serum should be infused nimmediately; at localized form – it’s possible waiting the reception of results nof bacterioscopy, otolaryngology’s-review etc., but under condition of constant nsurveillance in hospital; on diphtheritic croup – infusion of serum is nobligatory if this diagnosis is not refused after carrying out of intensive ncure during 1-1,5 hours.

For intensifying action of nSerum intramuscularly recommended infusion once a day 25 % of a solution of nmagnesium sulfates right after beginning of serotherapy.

Pathogenetic treatment is ndirected on desintoxication, restoration of hemodynamic and elimination of nadrenal gland insufficiency. Desintoxication therapy provides intravenous ninfusion of 10 % solution of glucose with insulin, albuminous preparations and ncolloid solutions in the ratio 1:1. A liquid is infused at the rate of 20-30 nmL/kg of mass. Diuretic agents, are indicated under the control of arterial npressure and diuresis.

For improvement of tissue nmetabolisms cocarboxylase, acidum ascorbinicum, a nicotinic acid, ATP are nindicated. The nicotinic acid decreases also an influence of diphtheritic ntoxin, and ascorbic – stimulates imunogenesis and function of cortex of the nadrenal glands.

Prednisolonum (2-3 mg/kg) or Hidrocortizonum (5-10 mg/kg per day) are nprescribed to the patient with widespread and toxic forms of diphtheria with nthe purpose of replaceable, anti-inflammatory and hyposensibilisative treatment nfor 5-6 days. In the first 2-3 days Glucocorticoides are infused in vein, theper os. In case of hypertoxic and hemoragic forms the daily dose of Prednisolonum nis enlarged up to 5-20 mg/kg according to stage of shock.

At toxic form of diphteria, since the first day there is indicated 0,1 % nsolution of Strychninum of Sodium nitritum (0,5-1,5 mL subcutaneously) during n2-3 weeks and more. Strychninum stimulates tone of the central nervous system, nstimulates respiratory and vasomotor centers, tones up sceletal muscles and a nmyocardium, stimulates oxidant-recreated processes in myocardium. Use of nCordiaminum, Corazolum raise a tone of organs of circulation. At cases of DIC nfor desagrigation, except Reopolyglucini, indicate antihistamines, nvasodilators, Trentalum, Ksantinoli. For reception of anticoagulative effect ninfuse Heparini (150-400 UN/kg  per day). Inhibitors of proteases are nrecommended.

Antibacterial therapy is prescribed with the purpose to impact oCorynebacterias diphtherias and secondary flora. It is expedient to apply nBenzylpenicilini, Tetracyclinums, Cefalosporines, Erythromicini.

Treatment of patients with diphtheria of larynx. Patogenic treatment is indicated: nSibazonum (Seduxenum) and etc. Oxygen therapy is provided. In case of a nstenosis of larynx without respiratory failure the good effect gives a warm nsoda drink, Sinapismuses and etc. hyposensibilisative preparations (Dimedrolum, nPipolfeni, Tavegili etc.) are used to decrease the edema of mucous, locally nantiedema and anti-inflammative therapy in aerosols (inhalations) is nprescribed.

Complex treatment provides also indication of Glucocorticosteroides, iparticular Prednisolonum (2-3 mg/kg per day), which, except for nanti-inflammatory action, assist decrease of edema of larynx, reduce a npermeability of wall of capillaries and exudation. Half of daily dose is ninfused intravenous or in muscle, the rest is given per os. After prescriptions ndesintoxicative therapy will carry out. Antibiotics of wide spectrum action are nprescribed. If conservative treatment is not effective, operative measures are nused.

Triad of signs to be the indications to initial intubations n(tracheostoma):

а) Paradoxical pulse n(inspiratory asystolia of Raufus); b) sign of Baie: continuous contractiosternocleidomastoideus muscles during  inspiration; c) proof cianosis of nlabiums and face. In case of a localized croup – long nasotracheal intubation, nat a wide-spread descending croup tracheostomy with the following drainage of ntrachea and bronchuses are indicated.

Treatment of complications. At myocarditis optimum duration of nthe bed period regime is near 3-4 weeks. There are indicated Strychninum (a nlong course); solution of glucose with cocarboxylase, Acidum ascorbinicum, ATP, ncalcium pangamatis, agents which influence on tissue metabolism (a nmethandrostenolone, a potassium Orotatis). At serious and medium myocarditis nPrednisolonum per os and parenteraly (in a daily dose 40-60 mg) is recommended. nIntroduction of cardiac glicosodes is supposed only at manifests of heart ninsufficiency without disorders of contraction. Anticoagulants of indirect naction are prescribed for prophylaxis of tromboembolitic complications (Dicumarinum, nNeodicoumarin, Pelentanum).

The patient with diphtheric polyneuritis should be indicated Strychninum, nvitamins of group B, glucocorticosteroides. In the recreating period an Oxazili ninside during 15-20 days, massage, medical gymnastics (cautiously), diathermy, ngalvanization, quartz are applied.

At attributes of defeat of respiratory muscles indicate antibiotics of nwide spectrum of action in the maximal doses for prophylaxis of pneumonia. nPatient can be transfer on apparatus respiration in conditions of departament nof reanimation after indications. Proceeding from action of diphtheritic toxias inhibitor of acetylcholinesterase, Proserini at neurologic complications is nindicated after fading acute displays of disease.

Treatment of toxygenic corinebacterias diphtherias carriers. At repeated allocation of nbacteria – antibiotics of tetracycline lines, Rifampicini are recommended. nAfter a seven-days course usually there comes sanitation. The basic attentioshould be payed to chronic disease of nasopharynx. Treatment begins with nfortifying (Methyluracilum, Pentoxylum, Aloe, vitamins) and hyposensibilisative nagents with physiotherapy (UHF, UF-radiation, ultrasound).

Duration of hospitalisation is determined by gravity of diphtheria and ncharacter of complications. If complications are not present, patients with the nlocalized form may discharge from the hospital at 12 – 14-th day of disease, nwith spread form at – 20 – 25-th (bed regime – 14 days). Patients with subtoxic nand toxic forms should be on bed regime 25-30 days; they may discharge at 30 – n40-th day of disease. In case of a toxic diphtheria II – III degree and serious ncurrent of disease the regime lasts 4-6 weeks and more. The obligatory ncondition for leaving the hospital of the patient with any form of a diphtheria nis negative result of two control inoculations received with an interval of 2 ndays.

 

A nposter from the United Kingdom advertising diphtheria immunisation (published nprior to 1962)

 

Prophylaxis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1992177/

The major manifestations of diphtheria can be nprevented in individual patients by immunization with formalin-inactivated ntoxin. Therefore, documentation of inadequate levels of antitoxin in large nproportion of the adult population in North America and Western Europe has ncaused great concern that a toxigenic strain introduced into these populations ncould cause a major outbreak of disease. Serum antitoxin levels can be measured nby toxieutralization tests in rabbit skin, in Vero cell culture, or by nhemagglutination, with roughly equivalent results. Concentrations of 0.1 –  0.01 n(international units) generally are thought to confer protection. For example, ndata from a recent outbreak showed that 90 % of clinical cases had antitoxilevels below 0.01 IU/mL, whereas 92 % of asymptomatic carriers had liters above n0.1 IU/mL. Following immunization, antitoxin levels decline slowly over time so nthat as many as 50 % of individuals over age 60 have serum liters below 0.01 nlU/mL. For this reason, booster doses of toxoid should be administered at n10-year intervals, to maintain antitoxin levels in the protective range.

Recommendations from the Immunization Practices Advisory Committee, npublished by CDC in 1991 are as follows.

For children from 6 weeks to 7 years of age: three 0.5-mL nintramuscular injections of (DPT) vaccine should be given at 4-8-week nintervals, beginning at 6-8 weeks of age, followed by a fourth dose 6-12 months nafter the third.

For persons 7 years or more of age: 0.5 mL Td (toxoid—adult) nis given twice at a 4-8-week interval, with a third dose 6-12 months later. nBecause the pertussis component of DPT is re­sponsible for most of its side neffects, and the risk of pertussis is much less after age 6, that component of nthe vaccine is omitted. Moreover, because subjects over age 7 have a higher nincidence of local and systemic reactions to the concentration of diphthe­ria ntoxoid in pediatric DPT vaccine (7-25 limit flocculation [Lf] units) and nbecause a lower dose of toxoid has been shown to induce protective levels of nantitoxin, the Td formulation of vaccine contains a maximum concentration of 2 nLf units of diph­theria toxoid. If the recommended sequence of primary immuni­zations nis interrupted, normal levels of immunity can be achieved simply by nadministering the remaining doses without need to restart the series.

Booster nimmunizations: children who have completed their primary immunization before age 4 nshould receive a booster dose of DPT at the time of school entry. Persons above n7 years of age should receive booster immunization with Td at 10-year nintervals. As a help to memory, this should be done at decade or mid-decade nintervals (e.g., ages 15, 25, 35, etc., or 20, 3О, 40, etc.). Travelers to areas where ndiphtheria is still endemic should be particularly careful to be sure their nimmunization is current. Although the recommended booster dose of 1.5-2.0 Lf nunits will increase antitoxin levels to above 0.01 IU in 90-100 % of previously nimmunized individuals, some authori­ties have recommended using 5 Lf units, nbecause antitoxin levels remain above 0.01 lU/mL for a longer period than with n2 Lf units.

Patients should receive toxoid nimmunization in the convalescent stage of their disease because clinical ninfection does not always induce adequate levels of antitoxin. Close contacts nwhose immunization status is incomplete or unclear should promptly receive a ndose of toxoid appropriate for their age, and complete the proper series of nimmunizations. In addition, they should receive prophylactic treatment with nerythromycin or penicillin, pending the results of pretreatment cultures. Givethese preventive measures, the prophylactic use of antitoxin is considered nunwarranted.