Plague 1. The first pandemic, known as the Justinian (AD 541-544), began in Egypt and spread throughout the Middle East and Mediterranean areas. Eventually, the entire known world was affected. By the 8th century, plague receded into scattered endemic areas. 2. The second pandemic began in 1347, when traders from central Asia introduced plague into ports of Sicily. This became the first epidemic, known as the , which killed over one third of the population of Europe. Later, following the Great Plague of London (1665), the disease subsided. 3. The third pandemic began in Hong Kong in 1894 and continues to the present.

 Y pestis:  nonmotile, non–spore-forming, pleomorphic, gram-negative coccobacillus.  The bacteria elaborate a lipopolysaccharide endotoxin, coagulase, and a fibrinolysin, which are the principal factors in the pathogenesis of this disease.

 Domestic and urban rats are the most important reservoirs for the plague bacillus, but field mice, cats, camels, chipmunks, prairie dogs, rabbits, and squirrels can be important animal reservoirs as well.  The most important vector for transmission of plague is the rat flea, Xenopsylla cheopis. Ticks and human lice have been identified as possible vectors.  Humans are accidental hosts in the natural cycle of this disease.  The classic mode of transmission to humans is a fleabite.  Alternately, broken skin serves as a portal when tissue or blood of an infected animal is handled (skinning or evisceration of infected animals).  occurs when pneumonia results from either hematogenous spread (secondary pneumonic plague) or inhalation (primary pneumonic plague) of organisms transmitted from animals or other humans.

Pathogenesis  The lesions seen in plague are the result of the local and systemic effects of plague endotoxins, several of which cause peripheral vascular collapse.  Disseminated intravascular coagulation (DIC) is often the fatal complication, more frequently in children than in adults.  Local lesions are characterized by a marked proliferation of Yersinia bacilli. Later there is toxin-induced necrosis of tissue; this causes vascular destruction with resultant hemorrhage.  Although the plague bacilli are actively phagocytized by macrophages, they are not killed; instead their bacillary toxins destroy the phagocytes, producing a diffuse amphophilic coagulum.  The pathology of plague is characterized by lymphangitis, lymphadenitis (bubo formation), and bacteremia, with spread of to the lung and other organs.

. Plague is now a rare infection of mankind and is limited to areas of sylvatic infection in sub-Saharan Africa, Southeast Asia, India and parts of China, South America, and the southwestern United States. Epidemics are unusual in recent decades and develop only when infected rats and fleas come into close proximity with humans in crowded urban areas.

Mortality/Morbidity:  has a 1-15% mortality rate in treated cases and a 40-60% mortality rate in untreated cases.  Septicemic plague (primary or secondary) has a 40% mortality rate in treated cases and 100% mortality in untreated cases.  Pneumonic plague (primary or secondary) has 100% mortality if not treated within the first 24 hours of infection.

1 History:  Bubonic plague o Patients most commonly present with this form of plague. o The incubation usually lasts 2-6 days. o Patients have a sudden onset of high fever 40°C, chills, and headache. o Patients also experience body aches, extreme exhaustion, weakness, abdominal pain, and/or diarrhea. o Patients with plague may complain of sleep disturbance, vertigo, and loss of memory. Weakness, delirium, stupor, ataxia, and speech disorders also may occur. These manifestations are due to the effects of endotoxin on the brain. o Vesicles may be observed at the site of the infected flea bite. o Buboes (a group of regional nodes), unilateral, adherent, extremely tender, can vary from 2-10 cm in size, with erythema and increased warmth of the overlying skin. o Femoral lymph nodes are most commonly involved. The affected limb may be in a position of flexion, abduction, and external rotation. o Enlargement of the buboes leads to rupture (in 10 days) and discharge of malodorous pus. o With advanced disease, pustules, carbuncles, eschar, or papules may be observed in areas of the skin drained by the involved lymph nodes. A generalized papular rash of the hands and feet may be observed. o Hepatomegaly and splenomegaly often occur, causing tenderness.

 Meningeal plague o Primary plague meningitis has occurred rarely o Most cases of plague with meningeal involvement closely resemble pyogenic meningitis and usually develop 9-15 days after inadequate treatment of bubonic plague. o Starting with a stiff neck and headaches, convulsions and then coma develop. o The cerebrospinal fluid is under pressure and the bacteria may be recovered by lumbar puncture.

 Primary pneumonic plague o Primary pneumonic plague begins as a lobular pneumonia with proteinaceous effusion in the alveoli o The alveolar walls undergo necrosis followed by hemorrhage. This process spreads and becomes confluent, involving first one lobe and then multiple lobes with hemorrhagic exudate in the alveoli and bronchi. o The bronchial and hilar nodes become involved, and hemorrhages and a fibrinopurulent pleuritis may overlie the infected lung. o Pneumonic plague is highly contagious and transmitted by aerosol droplets. o Patients have an abrupt onset of fever and chills, accompanied by cough, chest pain, dyspnea, productive purulent sputum, or hemoptysis. o Buboes may or may not appear in primary pneumonic plague. o Plague spreads rapidly in the lungs and causes acute pulmonary insufficiency, sepsis, and toxemic shock.

. Secondary pneumonic plague o results from hematogenous dissemination in bubonic plague. The lungs are more diffusely involved than in the primary form and bacilli are more numerous in the interstitium. The radiological findings in pneumonic plague, either primary or secondary, o are nonspecific and result from the pathological changes of rapidly developing pulmonary consolidation, necrosis, and hemorrhage.

2 o Initial radiographs of the chest may show patchy segmental or lobar pneumonia similar to pneumococcal pneumonia. o Consolidation may progress rapidly within a matter of hours or days often to more generalized patchy lobular pneumonitis involving multiple lobes of the same or both lungs.

 Primary septicemic plague o Septicemia rapidly ensues, with extensive damage to the endothelium of blood vessels and lymphatics. o Hemorrhages occur in many parts of the body, both in the skin and beneath mucous and serous membranes. o Blood-stained collections of fluid develop in the pleural and peritoneal cavities. o Marked visceral congestion involves the liver, spleen, heart, brain, meninges, and other organs. The spleen is often considerably enlarged. The heart is dilated and flabby, with severe toxic softening of the myocardium and hemorrhages beneath the endocardium and pericardium. o Patients experience nausea, vomiting, abdominal pain, and diarrhea. (Diarrhea may be the predominant symptom.) o Patients have a toxic appearance and may present with tachycardia, tachypnea, and hypotension, hypothermia is common. o Generalized purpura may be observed and can progress to necrosis and gangrene of the distal extremities. o Buboes are not observed with septicemic plague. o This form of plague is associated with a high mortality rate.

Lab.  Leucocytosis with a predominance of neutrophils is observed, and the degree of leucocytosis is proportional to the severity of illness. Leukemoid reactions may be observed, more commonly in children.  Peripheral blood smear shows toxic granulations and Dohle bodies.  Thrombocytopenia is common, and levels of fibrin degradation products may be elevated.  Serum transaminase and bilirubin levels may be elevated.  Proteinuria may be present, and renal function test findings may be abnormal.  Hypoglycemia may be observed.

 Plague is diagnosed by identification of (characteristic bipolar, pleomorphic bacilli using Gram's stain)  should be examined smears of: o seropurulent material aspirated from the bubo o blood, sputum, or cerebrospinal fluid  Culture results are often positive for Y pestis.  Serological testing to demonstrate plague antibodies include: o indirect hemagglutination, o direct immunofluorescence o ELISA (IgM and IgG), o radioimmunoassay. o PCR testing of fluid or cultures may aid in rapid diagnosis.

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3 o Place all patients thought to have plague and signs of pneumonia in strict respiratory isolation for 48-72 hours after starting antibiotic therapy. o Report patients thought to have plague to the local health department and to the World Health Organization. o Alert laboratory personnel to the possibility of the diagnosis of plague. All fluid specimens must be handled with gloves and mask to prevent aerosolization of the infected fluids.

 Streptomycin is the preferred drug of choice to treat plague. In patients who are allergic to streptomycin or who cannot tolerate streptomycin, doxycycline is a reasonable alternative.  Chloramphenicol is the preferred drug of choice in meningeal plague or for patients with hypotension. In patients with hypotension, intramuscularly administered streptomycin may be poorly absorbed.  Resistance of Y pestis to streptomycin, gentamicin, doxycycline, and chloramphenicol is very rare. No indication of emerging resistance during antibiotic therapy has been reported.

 Prophylactic antibiotic therapy o The CDC recommends administering prophylactic antibiotics for a short time to people who have been exposed to the bites of potentially infected rodent fleas during a plague outbreak. o Prophylactic antibiotic therapy is recommended for persons who have handled an animal known to be infected with the plague bacterium. o Prophylactic antibiotic therapy is recommended for persons who have had close exposure to a person or an animal thought to have pneumonic plague. o Preferred antibiotics for prophylaxis against plague are doxycycline 100 mg PO q12h for 14-21 days (for patients >8 y) and trimethoprim 160 mg/sulfamethoxazole 800 mg PO q12h for 14-21 days.  Plague vaccine o A licensed, killed, whole-cell vaccine is available to protect humans against bubonic, but not against primary pneumonic, plague. o Vaccination is of limited use. High risk groups include military troops and other field personnel that work in plague endemic areas in which exposure to rats and fleas cannot be controlled. o Plague vaccine is recommended for field workers in areas endemic for plague and for scientists and laboratory personnel who routinely work with the plague bacterium.

Treatment regiments are as follows: Adults Preferred choices Streptomycin, 1 gm IM twice daily for 10 days or Gentamicin, 5 mg/kg IM or IV once daily or 2 mg/kg loading dose followed by 1.7 mg/kg IM or IV 3 times daily for 10 days.

Alternative choices include Doxycycline, 100 mg IV twice daily or 200 mg IV once daily for 10 days, Ciprofloxacin, 400 mg IV twice daily for 10 days, or Chloramphenicol, 25 mg/kg IV 4 times daily for 10 days.

Children Preferred choices include Streptomycin, 15 mg/kg IM twice daily (maximum daily dose, 2 gm) or Gentamicin 2.5 mg/kg IM or IV 3 times daily for 10 days.

Alternative choices include 4 Doxycycline >45 kg, give adult dosage, < 45 kg, give 2.2 mg/kg IV twice daily for 10 days (maximum, 200 mg/day), Ciprofloxacin, 15 mg/kg IV twice daily for 10 days (maximum daily dose, 1 gm), or Chloramphenicol, 25 mg/kg IV 4 times daily for 10 days (maximum daily dos3 4 gm. In the event of mass exposure and the need for post-exposure prophylaxis, the regiment for adults is: - adults preferred choice: o Doxycycline, 100 mg PO twice daily for 7 days or o Ciprofloxacin, 500 mg PO twice daily for 7 days. - alternative choice: o Chloramphenicol, 25 mg/kg PO 4 times daily for 7 days. - For Children preferred choice: o Doxycycline, if >45 kg, give adult dosage; if < 45 kg, give 2.2 mg/kg PO twice daily for 7 days or o Ciprofloxacin, 20 mg/kg PO twice daily for 7 days (maximum daily dose, 1 gm). - An alternative choice is o Chloramphenicol, 25 mg/kg PO 4 times daily for 7 days (maximum daily dose, 4 gm). Plague may be spread through droplet contact. . All patients with plague should be isolated for the first 48 hours after the initiation of treatment. . Special care must be taken in handling blood and bubo discharge. . If pneumonic plague is present, strict, rigidly enforced respiratory isolation procedures must be followed, including the use of gowns, gloves and eye protection. . Patients with pneumonia must be isolated until they have completed at least 4 days of antibiotic therapy. . If patients have no pneumonia or draining lesions at 48 hours, they may be taken out of strict isolation.

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