Plague is an acute or chronic disease of wild and commensal rodents transmissible among these lower animal hosts and to man through the bite.of infected ectoparasites. The infection in man is acute and frequently fulminant and usually is characterized by abrupt onset of high fever, lymphadenopathy near the site of exposure, bacteremia, and prostration. Secondary or embolic pneumonia may result in direct respiratory spread of the disease from man to man. Thus, two clinical types of human infection are recognized: bubonic plague, characterized by either regional lymphadenopathy or bacteremia wherein organisms invade the blood by way of the lymphatics and produce overwhelming sepsis, and primary plague pneumonia.
Pasteurella pestis is a nonmotile, aerobic gram-negative bacillus that grows readily but slowly on artificial media. Small, convex dew- drop colonies become grayish and present a surface appearance like that of beaten copper after 48 hours’ incubation at 37° C. on blood agar. Virulent organisms are sticky because of the presence of a protein capsule. In liquid media, a surface pellicle and stalactites are characteristic. P. pestis is highly virulent for a variety of laboratory animals. The micro-organisms may be seen on microscopy of suitably stained node impressions, peritoneal exudate, and peripheral blood of these , hosts as coccoid or large ovoid “safety-pin” bacilli.
This bipolar staining is best demonstrated with Giemsa or Wayson’s stain, and may be conspicuous in lymph node aspirates and sputum of infected human beings. The organism is destroyed quickly by sunlight and common chemical disinfectants and is noninfectious after 15 minutes at 55° C. P. pestis may survive for several weeks in dry flea feces and human sputum, and may be kept viable and virulent in the frozen state for months. Although streptomycin-resistant mutants have been encountered in experimental plague infections, all naturally occurring human strains of P. pestis studied to date are inhibited in vitro by low concentrations of streptomycin, chloramphenicol, and the tetracyclines.
Incidence and Prevalence.
The first adequate description of widespread disease deals with an outbreak of plague in the •Egyptian port of Pelusium in 542 a.d. During the next 50 years, plague spread widely into Asia and Europe and it has been estimated that 100 million people perished at that time. Plague assumed catastrophic proportions again during the fourteenth century when it appeared not only >n Europe and the Middle East but also in China and India. Pneumonic plague was prominent in this pandemic, which, for unclear reasons, became known as the “Black Death.” In Europe alone, 25 million, or one fourth of the population, succumbed. The spread of plague resulted in the establishment of numerous widely distributed permanent foci among rodent populations.
During recent years, human plague has occurred in China, Vietnam, Burma, Indonesia, India, Iran, the Malagasy Republic, Central and South Africa, the United States, and several countries of South America. There has been a continuing decline in the incidence of human plague, however, and, in many instances, this decrease in incidence is unquestionably spontaneous. Certain endemic areas are characterized by a constant low human case rate resulting from sporadic infections that occur as a result of man’s accidental contact with wild rodent foci. In the United States between 1908 and 1951, only 91 human plague infections associated with wild rodents were distributed over 15 western states.
The ecology of plague varies from one region to another, and the extent to which man is affected by enzootic infections is determined in part by the proximity of human and rodent habitations and the bionomics of rodent ectoparasites. Although ticks and lice are capable of transmitting P. pestis to susceptible animals, practically speaking, the important vectors are fleas. Occasionally man contracts plague by handling the carcass of an infected animal. Epidemics of plague usually arise from infected commensal rats such as Rattus rattus and Rattus norvegicus, the causative organism being transmitted to man by Xenopsylla cheopis, the common rat flea.
There is general agreement that sylvatic foci of plague infection among so-called wild rodents (mice, field rats, gerbils, ground squirrels) accounts for the persistence of this disease in endemic areas. In some instances, man’s agricultural pursuits into sylvatic foci may result in outbreaks of human plague, and there is ample evidence of an interchange of fleas between commensal and wild rodent species. Flea-borne plague in man is usually of the bubonic variety, and as such does not represent a serious risk to other human beings. By contrast, plague pneumonia secondary to bacteremia may initiate a series of direct transmissions to susceptible contacts in whom the disease is manifest by a fulminant primary pneumonia.
Primarypneumonic plague may spread among a susceptible human population with alarming rapidity.Age and sex distribution of plague is dependent upon the nature of rodent foci and the habits of the human population at risk. Thus, domestic rat plague will be distributed evenly among both sexes of all ages when the home is infested with rat fleas. When field rodents constitute the source of infection, the disease will occur predominantly among field workers.
Evidence of infection is usually not present at the portal of entry into the skin, although a small pustule is observed in a few patients with bubonic plague. Similarly, lymphatics leading to regional nodes are grossly normal. The primary bubo is usually enlarged, exquisitely tender, and surrounded by a broad zone of subcutaneous edema. There is an intense hemorrhagic inflammatory reaction with infiltration of poly- nuclear cells. As the inflammation progresses, necrosis and suppuration of the bubo occur. There is a characteristic gelatinous edema of contiguous connective tissue and dilatation of small blood vessels.
Occasionally, infection of the oropharyngeal mucous membrane will lead to tonsillar or mediastinal reaction of the type seen in lymph nodes. Pathologic changes noted in other organ systems can be ascribed to small blood vessel disease, as evidenced by hemorrhages in serous membranes and gastrointestinal mucosa. In addition, degenerative changes of renal tubular epithelium and parenchymal cells of the liver are frequent. There may be slight enlargement of the liver and spleen. Vascular congestion of the meninges is accompanied by cerebral edema.
Secondary or embolic plague pneumonia is characterized by perivascular foci of inflammatory cells and colonies of P. pestis. As the disease progresses, distinction from primary plague infection of the lung is less obvious, and both may show gradation from lobar pneumonia to lobar consolidation. It is not unusual for several lobes to become involved within a period of 24 to 48 hours. In all instances, reaction in the lung is intense, there being cellular infiltration, gross hemorrhage, and copious exudation of watery sputum. There is overwhelming growth of plague bacilli in the lung that can be readily demonstrated in impression smears of cut lung surface. Bronchial lymph nodes are usually enlarged and hyperemic.
Following the ingestion of plague bacilli, the proximal digestive tract of the flea becomes obstructed as organisms multiply in the proventriculus. Refeeding results in regurgitation of the freshly ingested human blood as well as P. pestis into the feeding site. Organisms are then carried to regional lymph nodes, where a local inflammatory reaction leads to the formation of a bubo. In most instances, bacteremia occurs early in the disease and may assume enormous proportions in fulminant infections. Plague pneumonia is associated with the production of infectious droplets and respiratory spread of
- pestis, Epidemiologic studies suggest that intimate contact is a prerequisite to successful respiratory transmission of this organism,- and the nature of the primary lung lesion favors spread by particles of small size.
Although much has been said about intoxication in human plague infection, evidence of specific toxin activity in human beings is wanting. Extraction of virulent and attenuated strains -of P. pestis has revealed the presence of a water- soluble toxic substance that is highly lethal for Swiss mice. Although this material is antigenic in laboratory animals and- antibodies may be demonstrated in the sera of patients recovered from plague, its role in the pathogenesis of plague has not been established.
Most plague infections make their appearance abruptly with high fever, tachycardia, malaise, and aching of the extremities and back. Temperature usually rises to 103 or 104° F. within a few hours of onset, and the patient has the general appearance of profound illness, with flushed face and anxious expression. As the disease progresses, delirium may become a prominent feature of the clinical syndrome, and anxiety gives way to depression.
The incubation period in bubonic plague varies from one to six days in most instances and progresses to fulminant bacteremia, death ensuing within three to five days of the onset of symptoms. The case fatality in untreated bur bonic plague is variously estimated at 60 to 90 per cent. Regional lymphadenopathy or buboes of flea-borne plague are found in the groin in more than 50 per cent of patients with this form of the disease. Femoral and inguinal buboes are followed in frequency by axillary and cervical node involvement, The site of infection is influenced by the nature of exposure to vectors, there being a high frequency of lower extremity exposure among working adults and axillary and cervical buboes among children exposed as they sleep in a flea- infested dwelling.
The involved node may not be greatly enlarged but is invariably painful and exquisitely tender. Within a few hours, there is periadenitis with edema of surrounding tissue. Buboes may involute slowly or suppurate with discharge of necrotic material in patients who survive the acute phase of infection. When bacteremia progresses relentlessly, the clinical picture is one of overwhelming sepsis, and death is associated with peripheral vascular collapse.
Plague pneumonia acquired as a result of respiratory spread of P. pestis is even more fulminant, untreated patients rarely surviving for more than three days. The disease is characterized by an explosive onset of high fever, tachycardia, tachypnea, and restlessness. Flushing of the skin, conjunctival suffusion, and anxious expression are common. Headache and the early phases of illness, the paucity of signs is disproportionate to the obvious severity of the infection. Cough may be absent until six or more hours have passed. Subjective symptoms referable to the chest may be absent, or the patient may complain of pleural pain or dull substernal oppression.
Physical signs of. pneumonitis may be lacking at this time; however, as the disease progresses, rales, suppressed breathing, and impaired percussion appear. Signs of consolidation are not encountered frequently until after therapy has been instituted. The general clinical state rapidly deteriorates, and patients with this disease are gravely ill after 10 to 15 hours of fever. The patient may find it difficult to produce more than small amounts of sputum in the early hours of illness; however, blood-tinged sputum usually appears within the first 12 hours. Bloody, frothy, liquid sputum typical of plague pneumonia is produced in large quantities late in the disease at a time when the prognosis is uniformly poor.
Peripheral blood leukocytosis with total counts of 12,000 to 15,000 and neutrophilia usually occur in both types of human plague. There is elevation of the erythrocyte sedimentation rate, but other hematologic abnormalities have not been observed. Proteinuria and mild hematuria may accompany the acute febrile phase of plague.
The clinical diagnosis of plague is confirmed by conventional bacteriologic techniques and inoculation of susceptible laboratory animals. P. pestis may be isolated in pure culture after 48 to 96 hours from bubo aspirates, blood, and sputum, using blood agar and infusion broth. Inoculation of these materials into mice or guinea pigs produces bacteremia and death of the animal in two to five days. A smear of heart’s blood of these animals will reveal numerous bipolar staining rods.
In all instances, however, a tentative diagnosis of plague must be made on clinic&l and epidemiologic grounds, there being dire consequences of a missed diagnosis, especially of plague pneumonia. Careful examination of stained smears of bubo aspirates or sputum will usually reveal the presence of small gram-negative bacilli, and proper isolation precautions and specific therapy must be based on the judgment of this examination. Stained smears from organs of cadavers in cases of sudden death in plague endemic areas should be examined with great diligence to avoid catastrophic spread of this disease.
Patients recovering from plague develop specific antibodies that may be demonstrated in con- valescent-phase serum by bacterial agglutination, agglutination of erythrocytes sensitized with capsular antigen, complement-fixation, and mouse protection tests. Antibodies make their appearance early in the second week of disease and continue to rise up to the fourth or fifth week. In all cases, serodiagnosis is retrospective but of value in establishing the presence of infection with P.
Plague infections in man must be differentiated from tularemia, lymphogranuloma venereum, ar d other causes of localized lymphadenopathy. The disease is frequently fluenza, enteric fevers, and various causes of acute pneumonia, among them Klebsiella, staphylococcal, tularemia, and viral infections of the lung. In the absence of buboes or pneumonia, bacteremia owing to a variety of gram-negative organisms may resemble acute septicemic plague.
You Must Know Diseases Plague Treatment And Management.
P. pestis is readily inhibited in vitro by relatively small concentrations of streptomycin, chloramphenicol, and the tetracyclines. The disease responds readily when antimicrobial therapy is1 started during the early phase of illness, but it rapidly becomes refractory to specific treatment as it progresses. In view of the ease and uniform success of early therapy, delay in diagnosis and administration of chemotherapy is a grave error in clinical judgment. Pneumonic plague is uniformly fatal, and becomes difficult to treat after the twelfth to fifteenth hour of fever. Bubonic plague is generally less severe, but may progress to death with equal swiftness.
Early studies with sulfonamides revealed that mortality from bubonic plague could be reduced to 5 to 20 per cent by the administration of sulfadiazine or sulfamerazine at the rate of 12 grams daily for four to seven days. These drugs were found to be ineffective in plague pneumonia.
Streptomycin or the broad-spectrum antimicrobials represent the therapy of choice in all plague infections. Streptomycin should be administered parenterally at the rate of 4 grams daily for two days followed by 8 to 10 grams given over a period of five additional days. Chloramphenicol should be administered at the rate of 6 to 8 grams daily for the first 48 hours followed by 3 grams (50 to 75 mg. per kilogram) daily for a total dosage of 20 to 25 grams. Chloramphenicol should be given intravenously and orally during the first 48 hours of therapy if the latter route of administration is feasible. Tetracyclines should be administered in a similar, manner, large doses (4 to 6 grams daily) being given during the first 48 hours of therapy. Intravenous therapy during the first 24 hours is mandatory in severely ill patients but should be supplemented by oral administration of the drug if “this is tolerated by the patient.
When specific therapy is not instituted within the first 15 hours of overt illness in plague pneumonia, antimicrobial therapy usually will not favorably alter the outcome of the disease.Supportive care includes the use of intravenous fluid therapy, pressor drugs to support failing peripheral circulation, and oxygen therapy when respiratory function has been compromised by widespread pneumonitis. Tracheostomy frequently results in improved pulmonary function and facilitates care of patients severely ill with primary respiratory disease.
Prevention of’ plague is best accomplished by eliminating endemic foci of rodent infection. Improvement in living standards is usually associated with spontaneous disappearance of this disease or at least its confinement to sylvatic foci. However, there are many areas where such an evolution is not likely to occur and sylvatic foci will probably always exist. Under such circumstances, three general approaches plague control are available.
In practice, rodent control has proved to be the least effective method in most endemic regions, primarily because human living standards cannot be sufficiently improved Rodenticides in common use include sodium fluoroacetate (1080), arsenic trioxide, red squill, alpha- naphthyl thiourea (ANTU), and anticoagulants such as warfarin. In underdeveloped areas, vector control with dichlorodiphenyltrichloroethane (DDT) and other insecticides such as benzene hexachloride, chlordane, arid dieldrin is probably the most effective single control method. The residual effect of 10 per cent DDT dust or 5 per cent spray dispersed around rat habitations and human dwellings is sufficient to reduce sharply the flea populations and thus eliminate large numbers of vectors.
Finally, although millions of human beings have been inoculated with living, attenuated or formalin-killed plague vaccines, the protective effect of these immune prophylactics has not been assessed adequately. However, there is evidence to support the concept that the production of specific antibodies in man is associated with a significant degree of resistance to plague infection. Protection of human populations against plague is best assured in endemic areas when all available control measures are employed.