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					                                       PLAGUE
CASE DEFINITION

 Clinical case description:
 Disease characterized by rapid onset of fever, chills, headache, severe malaise, prostration
 with
    • Bubonic form: extreme painful swelling of lymph nodes (buboes)
    • Pneumonic form: cough with blood-stained sputum, chest pain, difficult breathing
    • Septicemia form: toxic changes in the patient.

 Laboratory criteria for diagnosis:
    • Giemsa smear should be positive
    • Direct fluorescent antibody testing of smears (for anti-F1 antibody)
    • PCR test
    • 4 fold increase in antibody titres against F1 antigen (by PHA tests)
    • Isolation of the bacteria by culture and phage lysis

 Case classification
       Suspect case: A case that meets the clinical case definition.
       Probable case: A suspect case with
          • Y.pestis F1 antigen detected in clinical materials by direct fluorescent
              antibody testing or by some other standardized antigen detection method,
              or
          • Isolate from a clinical specimen demonstrates biochemical reactions
              consistent with Y.pestis or PCR positivity, or
          • A single serum specimen is found positive for diagnostic levels of antibodies
              to Y.pestis F1 antigen, not explainable on the basis of prior infection or
              immunization
          • Epidemiological link with a confirmed case.
       Confirmed case: a suspected or probable case that is lab-confirmed
           • Isolate identified as Y. pestis by phage lysis or cultures; or
           • A significant (4-fold) change in antibody titre to the F1 antigen in paired
              serum specimens.




EPIDEMIOLOGY (see Fig 1)
 Agent: The agent is a gram-negative cocco-bacilli – Yersinia pestis; which has a bipolar
 (safety pin) appearance on aniline staining. Sunlight, high temperatures and desiccation
 have a destructive effect, and ordinary disinfectants such as Lysol and preparations
 containing chlorine kill it within 1 to 10 minutes.

 Reservoir: Wild rodents are the natural reservoirs. In India the reservoirs are mainly the
 wild rats – Bandicoota bengalensis, Tatera indica etc. They are susceptible to infection but


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     not the disease. Others like wild squirrels, rabbits and wild carnivores may also be a
     source of infection. Plague remains in the wild due to various factors – e.g. rat – flea –rat
     cycle; survival of fleas in rat burrows for long periods of time; survival of plague bacilli in
     the rat burrows, eating of infected rodents by carnivore, etc.

     Fig 1 – Epidemiology of plague


                      DOMESTIC CYCLE                                    SYLVATIC CYCLE


                                                                                     Wild
       Bioterrorism           Uninfected                                            rodent
                              host (man)

                                                                        Flea                      Flea
                                              Domestic / Peri-
                                              domestic rodent
                                                                                      Wild
                                                   Handling infected                 rodent
                                                       tissues
                              Infected host
                                  (man)
  Droplet
 infection


                              Diseased host




Pneumonic                       Bubonic                              Septicemic
  plague                         plague                                plague




              Recovery                           Death




                                                                                                       7
 Vector: The main vector is the Oriental rat flea – Xenopsylla cheopis

 Transmission: There are at least 6 potential modes of transmission:
    1. Wild rodent > Flea > Peridomestic rodents > Flea > Domestic rodent > Flea > Humans
    2. Human with pneumonic plague > droplet infection > Humans
    3. Wild rodents > Flea > Humans (when humans enter the forests etc where the sylvatic cycle
       is maintained)
    4. Handling infected rodent tissue (wild / domestic) or any other infected material e.g. pus
       from buboes
    5. Domestic cats eat infected rodents > develop pneumonic plague > Droplet infection >
       Humans
    6. Plague bacilli > Bioterrorism > Humans

 Host: All ages and both sexes are susceptible. People with occupations like hunting and
 grazing are more susceptible. There is no natural immunity and one can contract the
 disease even after previous illness.

 Environment: Plague in North India is seasonal – higher chances in the winter. In the
 south, there are no definite seasonal trends. Any environmental condition that disturbs the
 rodent’s natural environment e.g. floods and causes the overlap between the wild rodents
 and the peridomestic rodents is a potential source for plague in humans.

 Incubation period: For Bubonic and septicemic plague – 2 to 6 days; for pneumonic
 plague – 1 to 3 days. The person is not infective during this period.

SIGNS AND SYMPTOMS:
 Bubonic plague: Fever, chills, headache, prostration and painful lymphadenitis (inguinal
 nodes are involved in 90% of the cases). The nodes swollen, inflamed and may
 suppurate. Specific treatment leads to resolution of the fever and general symptoms but
 the bubo remains painful and tender for weeks. If untreated, 50 – 60% die.
 Pneumonic plague: It may be primary or secondary. In primary, the host acquires it from
 another patient with pneumonic plague, while in the secondary form, the host acquires it
 secondary to a bubonic / septicemic plague. The symptoms in primary plague are onset of
 fever, chills, headache, prostration and cough 1 to 3 days after exposure to a case of
 pneumonic plague. Increasing chest pain, dyspnoea and hemoptysis become prominent
 as the disease rapidly progresses. In secondary pneumonic plague, the patient already
 has symptoms of either bubonic plague or septicemic plague and is already moribund
 before developing the signs and symptoms. The disease is fatal if the patients with
 pneumonic plague are untreated in the initial 18 – 24 hours.
 Common Symptoms/Syndromes of Human Plague

                                                                       Primary
     List of Symptoms      Bubonic               Septicaemic
                                                                       Pneumonic
     Sudden onset          +                     +                     +
     High Fever            +                     +                     +
     Bubo             +                          + -                   -
     Cough with blood -                          -                     +
     stained sputum




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 Septicemic plague: This is a rapidly progressive infection resulting in endotoxic shock,
 DIC, multi organ failure, ARDS etc. It leads to metastatic infection of other organ systems.
 Others: Other forms of plague are pharyngeal plague (symptomatic or asymptomatic
 colonization of the pharynx) and Meningeal plague (fever, headache, stiff neck, delirium
 and coma).

DIFFERENTIAL DIAGNOSIS:
 Bubonic plague: Strep / Staph lymphadenitis, lymphatic filariasis, infectious
 mononucleosis etc
 Septicemic plague: Any gram-negative septicemia
 Pneumonic plague: Any pneumonia

LABORATORY SPECIMENS
 When plague is suspected, clinical specimens should be collected urgently, and specific
 antimicrobial treatment begun without waiting for the laboratory report. The specimen to
 be collected depends on the type of plague. The details are given below. All specimens
 should be collected under aseptic conditions, put in sterile containers and transported by
 maintaining cold chain. Cary Blair media can be used as a transport media for any
 material that is to be cultured.

 A brief summary of specimens required is shown in table
 Clinical Presentation         Specimen
 Bubonic                       Bubo fluid / aspirate
                               Blood
                               Serum
 Pneumonic                     Bronchial/tracheal washing
                               Sputum
                               Blood
                               Serum
 Septicaemic                   Blood
 Post-mortem                   Biopsy from
                               Lymph nodes
                               Lungs
                               Bone marrow

 Precautions in Handling Specimens
 As these specimens are known or thought likely to contain infectious substances, the
 following precautions should be applied:
 •   Strict aseptic technique (gowns, gloves, masks)
 •   Wash hands before and after the collection of material
 •   Place the specimen aseptically in an appropriate sterile container
 •   Tightly close the container
 •   Label and date the container
 All handling specimens should be put on chemoprophylaxis.
 Packaging/Transportation of Specimen




                                                                                              9
 In accordance with currently accepted biosafety norms, Y.pestis is listed under Biosafety 2
 level. The details are given at the end of this chapter. Samples should be sent to the
 following laboratory with prior intimation.
 NICD
 22, Shamnath Marg,
 New Delhi – 110054
 Tel: 011 3913148 / 3971272 / 3971344
 Fax: 011 3922677 / 3946893
 Email: dirnicd@bol.net.in; dirnicd@del3.vsnl.net.in

 As plague is a public health emergency, the specimen should be sent by air to NICD.
 Either a special messenger should carry the specimen or it should be sent by air cargo
 after informing NICD officials about the details so that there is somebody at Delhi to
 receive the same.

CASE MANAGEMENT:
 Inj Streptomicin (30 mg/kg/day - up to a total of 2 g/day) im Q12H for 10 days.

 or
 Cap. Chloramphenicol (50mg/kg/day) Q6H for 10 days.

 or
 Cap Tetracycline (50mg / kg / day) Q6H for 10 days

 or
 Cap Doxycycline 200mg / day Q12H for 10 days.

 or
 Tab. Cotrimoxazole (10mg/kg/day) Q12H for 10 days

 Penicillins, Cephalosporins, Macrolides - These classes of antibiotics should not be
 used for the treatment of plague.

        Treatment of plague during pregnancy and in children
        The preferred antibiotic for treating plague in pregnancy is
        Gentamycin given intravenously (IV) or intramuscularly (IM).


 Other supportive measures maybe instituted to the hospitalized patients.
 Adequate isolation measures should be instituted. In the event of pneumonic or
 septicaemic plague, intravenous antibiotics should be given.

PREVENTION
 Chemoprophylaxis
   • To those people who are entering an area that has a known outbreak of plague or
     those health care personnel who would be handling plague material.
   • To those who have come in contact with plague patients, especially pneumonic
     plague.



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       •   Ideally the drugs for chemoprophylaxis should be given for 5 – 7 days from date of
           last exposure
       •   The drugs to be used for chemoprophylaxis are given below. Doxycycline has been
           the drug of choice for chemoprophylaxis.

 Immunisation during an outbreak has negligible value as the bacteria spreads very fast.
 Moreover, it is not fully protective, especially in pneumonic plague and finally the chances
 of adverse reactions are high.

 Anti flea measures – personal protection with repellants, dusting with Malathion (5%) or
 synthetic pyrethroids in rat burrows / houses (junction of floor and wall).

 Anti rodent measures – only during inter epidemic period. Sanitation and proper disposal
 of garbage, poisons (anticoagulants, aluminium phosphide, fumigants)

 Plague Prophylaxis Guidelines
 Drug                          Dosage                 Interval (hrs)         Route of
                                                                             Administration
 Tetracycline
       Adults                  1-2g/day               6                      PO
       Children 9              25-50mg/kg/day         6                      PO
 years
 Doxycycline
       Adults                  200mg/day              12                     PO
       Children 9              200mg/day              12                     PO
 years
 Sulfamethosazole/
  Trimethoprim
       Adults                  1.6g/day*              12                     PO
       Children 2              40mg/kg/day*           12                     PO
 years



SURVEILLANCE
 Plague surveillance is mainly laboratory based active surveillance. The various
 components of surveillance are:
    • Rodent surveillance
    • Flea surveillance
    • Sero surveillance among wild rodents and dogs
    • Clinical surveillance

 Details of this are given in the WHO Plague manual and are usually carried out by
 specialized plague surveillance units. What is important is to recognize the trigger events
 that are the precursors of a potential outbreak. These trigger events are:
    • Rat fall – more than one dead rat in a house, or more than one house with dead
        rats1

 1
     Where it has been ascertained that the deaths among the rats have not been due to poisoning.


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    •   Flea index more than one
    •   Positive serology in rodents / canines
    •   A suspected case of human plague.

 If any one of the trigger events is positive, then a potential outbreak should be suspected
 and appropriate authorities, including NICD should be informed immediately.

OUTBREAK INVESTIGATION AND MANAGEMENT
 In the event of an outbreak, it should be considered as a Public Health Emergency and a
 clear cut drill should be followed as given in Annex 2 under the guidance of an expert
 team from the State / NICD. The main steps are:

    •   Verification of the outbreak immediately
    •   Notification to the higher authorities
    •   Institution of containment measures
    •   Confirmation of the outbreak

 To summarize
 • Report suspected case to the next level and NICD. Also verify the case diagnosis by a
    clinician.
 • Collect clinical samples (before starting antibiotics) for confirming the outbreak. Send
    the material to the state as per guidelines given above. Collect also samples of rodents
    and fleas.
 • Do an epidemiological investigation
        o Active search for cases of plague – identify all cases by age, sex and history of
            contact or exposure. Also date of onset of illness and complications if any. Get
            the support of the community for this search.
        o Draw the epidemic curve and understand the dynamics of the outbreak,
            including the index case, the transmission and direction of spread and the
            susceptible population.
        o Analyse the data by time, place and person.
        o Calculate the attack rate and the case fatality ratio.
 • Simultaneously institute control mechanism
        o Case management of individual suspect cases
        o Hospitalise all suspect cases in isolation wards.
        o Avoid transportation of suspect pneumonic plague in public vehicles.
        o Institute standard precautions for bubonic / septicemic plague and droplet
            precautions for pneumonic plague.
        o Disinfection of all contaminated material

        For patients with pneumonic plague, strict isolation with precautions against
        airborne droplet spread is required (see…) until a period of at least 48 hours after
        completion of appropriate antibiotic therapy (usually ten days + 48 hours) and there
        is evidence of satisfactory clinical response

        o Chemoprophylaxis to all contacts
        o Minimise movement of people into and out of the village.




                                                                                           12
        o Anti flea measures especially in bubonic plague e.g. dusting of rodent burrows,
          disinsectation of clothes, dwelling etc. Not important if the outbreak is due to
          primary pneumonic plague.
        o Anti rodent measures minimised to sanitation and rat proofing the houses.
          Important in the case of bubonic plague outbreak. Not so with primary
          pneumonic plague outbreak. DO NOT KILL RATS DURING AN EPIDEMIC.
        o Educate the community about “dos and don’ts” – example is given below.
        o Keep the higher authorities informed through daily updates and then a final
          report at the end of the outbreak (20 days after last case)

CONCLUSIONS
 Plague is a rare disease in our country and outbreaks occurs periodically. However, an
 outbreak of plague has various implications, its high case fatality ratio attracts
 considerable fear among the public; its epidemic potential is a health manager’s
 nightmare and its economic implications makes it politically sensitive. And of late, it has
 been considered as an agent for biological warfare.

 Keeping in mind all these implications, an outbreak of plague has to be handled very
 sensitively and vigorously.




                                                                                               13
                                                                                  ANNEX 1
Packaging/Transportation of Specimen
     In accordance with currently accepted biosafety norms, Y.pestis is listed under
Biosafety 2 level. Therefore, the regulations of the WHO as contained in its publication
(WHO/EMC/97.3) “Guidelines for the Safe Transport of Infectious Substances and
Diagnostic Specimens” for shipping dangerous good (should) apply when the specimens
are to be shipped via air transport either domestic or international.
The requirements, in brief, are:
   •   A watertight primary receptacle
   •   A watertight secondary receptacle
   •   An absorbent material, which must be placed between the primary receptacle and
       the secondary packaging. The absorbing material must be adequate to absorb the
       entire contents of all primary receptacles.
   •   Must be at least 100 mm in the smallest overall external dimension
   •   Itemized list of contents must be enclosed.
   •   Receptacles must withstand, without leakage, internal pressure difference of not
       less than 95 kPa (0.09 bar, 13.8 lb/in2) and temperature range of –40oC to +55oC.
   •   Outside package must be marked with identification of the infectious substance,
       volume of contents, name, and telephone number of shipper.

All materials should be double-packaged in crush-proof and leak-proof containers.
Infectious agents, serum or cultures vessels should be labelled with alcohol-resistant,
permanent ink marker as to the contents and dated. The materials should be sealed with
Para film or tape to prevent inadvertent leakage and then wrapped with several layers of
absorbent material. The absorbent-wrapped materials are placed in a leak-proof bag,
soaked with disinfectant (quaternary ammonium or phenolic solutions) and sealed. The
sealed bag is then placed in the first of two crush-proof containers, sealed and placed into
the second crush-proof container. Depending on the specimen and the destination, the
double container is sent in a sealed box with or without coolant.

Do not use wet ice for packaging because it melts and leaks. Cool packs (plastic bags
containing frozen foam/refrigerant) are acceptable but must be placed in the box so that,
upon thawing they do not permit movement of materials within the box. Containers must
be especially well sealed if they are being shipped under dry ice conditions. Dry ice
evaporates, thus when packing, this must be taken into consideration.

Important parts of shipping are the proper labelling of the container and the inclusion of
the paper work that identifies the specimen(s), the clinical history or the epidemiologic
information, the sender’s identification and address, the purpose of which the specimen is
sent and the import/export licenses if necessary. The outside of the container must be
labelled with all the proper identification and biohazard warnings. If shipping with dry
ice, the box must be identified with the correct label.




                                                                                         14
                                                                                   ANNEX 2
                       OUTBREAK RESPONSE
                                                                Suspected case of plague
                                                        (bubonic / septicemic / pneumonic)



                                                        Immediate Verification by the MO
                              (based on history of exposure, clinical signs and symptoms)



                                                   Suspected plague



             Immediate notification                     Immediate institution of
             to District authorities                    containment measures


Notify State and       1. Send RRT                       1. Case management –
National                  immediately for                   appropriate antibiotic for 10
authorities               conducting                        days
immediately               epidemiological /              2. Hospitalize all suspect cases
                          clinical / laboratory          3. Active surveillance for new
                          investigation                     cases
                       2. Activate Epidemic              4. Chemoprophylaxis to all
                          control committee                 contacts
                       3. Set up a control room.         5. Flea control and sanitation
                       4. Mobilize drugs,                   measures in the event of
                          vehicles, manpower,               bubonic plague.
                          finances
                       5. Send lab specimens
                          to State / NICD


                                   Lab reports


                               Positive                   Negative



             •     National authorities to                 Investigate further to find out
                   notify to WHO                           cause of outbreak
             •     Intensify containment
                   measures further
             •     IEC


                                                                                             15
                                                                                    ANNEX 3
Hospital precautions
Standard patient-care precautions should be applied to management of all suspected
plague patients, and standard droplet precautions for those with suspect or presumptive
or confirmed pneumonic plague.


5.3   Standard Precautions
        Use Standard Precautions for the equivalent, for the care of all suspect
 plague patients.
 A. Handwashing
  (1) Wash hands after touching blood, body fluids, secretions, excretions, and
  contaminated items, whether or not gloves are worn. Wash hands immediately
  after gloves are removed, between patient contacts, and when otherwise
  indicated to avoid transfer of microorganisms to other patients or
  environments. It may be necessary to wash hands between tasks and
  procedures on the same patient to prevent cross-contamination of different
  body sites.
  (2) Use a plain (non-antimicrobial) soap for routine hand washing.
  (3) Use an antimicrobial agent or a waterless antiseptic agent for specific
  circumstances (e.g., control of outbreaks or hyperendemic infections), as
  defined by the infection control program.
 B. Gloves
  Wear gloves (clean, nonsterile gloves are adequate) when touching blood,
  body fluids, secretions, excretions, and contaminated items. Put on clean
  gloves just before touching mucous membranes and nonintact skin. Change
  gloves between tasks and procedures on the same patient after contact with
  material that may contain a high concentration of micro organisms. Remove
  gloves promptly after use, before touching noncontaminated items and
  environmental surfaces, and before going to another patient, and wash hands
  immediately to avoid transfer of microorganisms to other patients or
  environments.
 C. Mask, Eye Protection, Face Shield

      Wear a mask and eye protection or a face shield to protect mucous membranes
      of the eyes, nose, and mouth during procedures and patient-care activities that
      are likely to generate splashes or sprays of blood, body fluids, secretions, and
      excretions.
 D. Gown
      Wear a gown (a clean, nonsterile gown is adequate) to protect skin and to
      prevent soiling of clothing during procedures and patient-care activities that
      are likely to generate splashes or sprays of blood, body fluids, secretions, or
      excretions. Select a gown that is appropriate for the activity and amount of
      fluid likely to be encountered. Remove a soiled gown as promptly as possible,
      and wash hands to avoid transfer of microorganisms to other patients or



                                                                                         16
 environments.
E. Patient-Care Equipment
 Handle used patient-care equipment soiled with blood, body fluids, secretions,
 and excretions in a manner that prevents skin and mucous membrane
 exposures, contamination of clothing, and transfer of micro-organisms to other
 patients and environments. Ensure that reusable equipment is not used for the
 care of another patient until it has been cleaned and reprocessed appropriately.
 Ensure that single-use items are discarded properly.
F. Environmental Control
 Ensure that the hospital has adequate procedures for the routine care, cleaning,
 and disinfection of environmental surfaces, beds, bedrails, bedside equipment,
 and other frequently touched surfaces, and ensure that these procedures are
 being followed.
G. Linen
 Handle, transport, and process used linen soiled with blood, body fluids,
 secretions, and excretions in a manner that prevents skin and mucous
 membrane exposures and contamination of clothing, and that avoids transfer
 of microorganisms to other patients and environments.
H. Occupational Health and Blood-borne Pathogens
 (1) Take care to prevent injuries when using needles, scalpels, and other sharp
 instruments or devices; when handling sharp instruments after procedures;
 when cleaning used instruments; and when disposing of used needles. Never
 recap used needles, or otherwise manipulate them using both hands, or use
 any other technique that involves directing the point of a needle toward any
 part of the body; rather, use either a one-handed "scoop" technique or a
 mechanical device designed for holding the needle sheath. Do not remove
 used needles from disposable syringes by hand, and do not bend, break, or
 otherwise manipulate used needles by hand. Place used disposable syringes
 and needles, scalpel blades, and other sharp items in appropriate puncture-
 resistant containers, which are located as close as practical to the area in which
 the items were used, and place reusable syringes and needles in a puncture-
 resistant container for transport to the reprocessing area.
 (2) Use mouthpieces, resuscitation bags, or other ventilation devices as an
 alternative to mouth-to-mouth resuscitation methods in areas where the need
 for resuscitation is predictable.
I. Patient Placement
 Place a patient who contaminates the environment or who does not (or cannot
 be expected to) assist in maintaining appropriate hygiene or environmental
 control in a separate individual room. If a separate room is not available,
 consult with infection control professionals regarding patient placement or
 other alternatives.



                                                                                      17
5.4   Droplet Precautions

  In addition to Standard Precautions, use Droplet Precautions, or the
  equivalent, for a pneumonic plague patient known or suspected to be infected
  with micro organisms transmitted by droplets (large-particle droplets [larger
  than 5 µm in size] that can be generated by the patient during coughing,
  sneezing, talking, or the performance of procedures).
 A. Patient Placement
  Place the patient in an individual room. If an individual room is not available,
  place the patients of the same cluster cohorts together in a room (same
  symptoms, same date of onset) When a separate individual room is not
  available and cohorting is not achievable, maintain spatial separation of at least
  two (2) metres between the infected patient and other patients and visitors.
  Special air handling and ventilation are not necessary, and the door may
  remain open.
 B. Mask
  In addition to wearing a mask as outlined under Standard Precautions, wear a
  mask when working within 2 metres of the patient. (Logistically, some
  hospitals may want to implement the wearing of a mask to enter the room.)
 C. Patient Transport
        Restrict the movement and transport of the patient. If transport or
 movement is necessary, minimize patient dispersal of droplets by masking the
 patient.




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