Rat-bite fever is usually attributable to Streptobacillus moniliformis in the Americas, Europe, and Australia; in Asia, Spirillum minus is the commoner cause. Bites are increasingly common among child pet owners and pet-shop and laboratory workers. Both bacteria are commensals of rodents and their predators. After an incubation period less than 1 week, S. moniliformis causes sudden high fever, rigors, myalgia, petechial rash, and migratory reactive or septic polyarthritis with synovial effusions. Complications include fulminant septicaemia, endocarditis, pneumonia, and metastatic abscesses. S. minus infection (sodoku) has a longer incubation period with similarly high fever but concomitant exacerbation of the bite wound, local lymphadenopathy, papular rash, and arthralgia without effusions. In both diseases, fever subsides after a few days but may relapse repeatedly over months. Untreated mortality is about 10% for S. moniliformis and 2 to 10% for S. minus. S. moniliformis can be cultured (with some difficulty) and the diagnosis confirmed by polymerase chain reaction (PCR) methods and serology. S. minus cannot be confirmed by culture or serology but can be demonstrated microscopically in the bite wound and other tissues or by isolation in animals. Penicillin is the treatment of choice for both infections. Prevention is by controlling peridomestic rats and avoiding bites by pet or laboratory rodents.
Feral rodent populations are increasing worldwide and rat bites occur in impoverished infested rural and urban dwellings. Under these conditions, young children are often bitten while asleep and patients with diabetic or leprous neuropathy are particularly vulnerable. However, increasing numbers of rodents are now kept as pets and as laboratory animals, explaining why bites are becoming more common among pet owners and pet shop and laboratory workers. There are said to be at least 20 000 rat bites in the United States of America each year. Wild rats harbour a variety of other zoonotic pathogens including cryptosporidium, pasteurella, yersinia, listeria, coxiella, salmonella, leptospira, toxoplasma, and hantaviruses.
Streptobacillus moniliformis infection (streptobacillary rat-bite fever and Haverhill fever)
Streptobacillus moniliformis is part of the normal pharyngeal flora of 50 to 100% of wild and 10 to 100% of laboratory rats. It can be recovered from their nasopharynx, middle ear, saliva, and urine. In rodents it can cause septicaemia, pneumonia, conjunctivitis, polyarthritis, and abortion. It has been isolated from rats, mice, guinea pigs, gerbils, squirrels, and animals that feed on rodents such as cats, dogs, pigs, ferrets, and weasels. S. moniliformis infection is reported in monkeys, koalas, and turkeys.
S. moniliformis is named after the necklace-like filaments and chains with yeast-like swellings seen in mature cultures on solid media. It is a nonmotile pleomorphic filamentous Gram-negative rod, 1 to 5 µm long. Although it can be grown in ordinary blood culture media, it is ultrafastidious, microaerophilic, and slow-growing making it difficult to isolate. However, it thrives on trypticase soy agar enriched with 20% horse or rabbit blood, serum, or ascitic fluid under 8% carbon dioxide. In liquid media, ‘puff ball’ colonies appear in 2 to 7 days. In concentrations as low as 0.0125%, sodium polyanethol sulphonate (liquoid), a laboratory anticoagulant added to most commercial aerobic media, inhibits the growth of S. moniliformis. On agar, ‘fried-egg’ colonies appearing after 5 days culture signify L-phase variants that lack a cell wall and are therefore resistant to penicillin.
Streptobacillary rat-bite fever
As a cause of rat-bite fever, S. moniliformis is apparently much commoner than Spirillum minus in the Americas, Europe, and Australia. Despite its name, there is no history of a bite in 30% of cases. Bites or scratches by rodents or their predators, contact with mucous membranes (e.g. when pet owners kiss or share food with their rodents), or other contact with these mammals whether living or dead may result in infection. In some countries, 10% of those bitten by wild rats are infected. Formerly, most people with rat bites were children of poor families living in urban areas. A bite might not be suspected because it was inflicted while they were asleep. In the United States of America, 55% of those infected are children younger than 12 years old. Increasing numbers of people with rat-bite fever are pet owners and pet shop and laboratory staff. Human-to-human transmission has not been reported.
Named after a town in Massachusetts where there was an outbreak involving 86 cases in 1926, Haverhill fever follows ingestion of raw milk, food, or water contaminated by rats. An outbreak in a boarding school in England in 1983 affected 304 people, 43% of the school’s population, and was attributed to contamination of the water supply by rats.
Streptobacillary rat-bite fever
If transmission is by bite, the wound usually heals quickly with only trivial local inflammation or pustule formation.
The systemic illness starts suddenly after an incubation period that is usually less than 7 days, is often as short as 1 to 3 days, but is sometimes as long as 7 weeks. There is high fever with rigors, vomiting, severe headache, sore throat, myalgia, and muscle tenderness lasting 3 to 5 days. About 75% of patients develop a rash 1 to 8 days later. Discrete erythematous macules or papules, 1 to 4 mm in diameter, appear symmetrically on the lateral and extensor surfaces and over the joints. They are often most marked on the hands and feet (palms and soles) with associated petechiae, but may also occur on the face. Papules, vesicles, haemorrhagic vesicles, and pustules with scabs may develop. There is desquamation in about 20% of cases. Early in the illness, approximately one-half the patients develop an asymmetrical migratory subacute or chronic polyarthralgia or arthritis which is thought to be reactive (autoimmune). It usually involves the knees, ankles, elbows, shoulders, and hips and is often associated with sterile effusions. Far less commonly, a distinct streptobacillary septic (suppurative) arthritis affects single or multiple distal joints, most often the knee but also the fingers. Severe joint pain and tenderness may be the dominant symptom in patients with rat-bite fever. Diarrhoea and loss of weight are described in young children. Fever and other symptoms subside in a few days in treated cases, but fever may persist for 1 to 2 weeks, relapsing repeatedly over several months, and arthritis may persist for many months in those who are untreated. Severe infections can lead to bronchitis, pneumonia, pleural effusions, metastatic abscess formation (including cerebral abscess), endocarditis, myocarditis, pericarditis with effusion, subacute glomerulonephritis, interstitial nephritis, splenitis or splenic abscess, amnionitis, meningitis, hepatitis, systemic vasculitis, polyarteritis nodosa, and renal and multiorgan failure. Infective endocarditis, usually with underlying rheumatic or other valve disease, has been described.
Haverhill fever (erythema arthriticum epidemicum) follows a similar clinical course after the patient has drunk unpasteurized milk or contaminated water. Vomiting, stomatitis, and upper respiratory tract symptoms such as sore throat are said to be more prominent than in rat-bite fever.
Unlike Spirillum minus infection (sodoku, see below), the other cause of rat-bite fever, the incubation period is usually short, the bite wound heals permanently with little local lymphadenopathy, the rash is morbilliform or petechial, and arthritis is common. Depending on the geographical area, S. moniliformis infection must be distinguished from other acute fevers associated with rodent bites and contact, including lymphocytic choriomeningitis and other arenaviruses, hantaviruses, leptospirosis, melioidosis, tularaemia, plague, murine typhus, trench fever, and Pasteurella multocida. The polyarthritis may be confused with acute rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus, or Still’s disease. The acute febrile illness and exanthem may suggest other bacterial septicaemias such as meningococcaemia, rickettsial infections, and even secondary syphilis and in children, Kawasaki disease.
Fever after ingestion of raw milk should raise the possibility of brucellosis.
The diagnosis can be confirmed by culture of bite wounds, blood, synovial and pericardial fluid, skin blister fluid, or pus from abscesses, but the organism is ultrafastidious and slow-growing (see above). In patients with infective endocarditis the differential diagnosis of these slow-growing microaerophilic organism includes Haemophilus aphrophilus, Cardiobacterium hominis, Actinomyces actinomycetemcomitans, and Eikenella corrodens. A high or rising titre of agglutinins, complement-fixing or fluorescent antibodies, may be detected between 2 and 3 weeks. Polymerase chain reaction based on 16S rRNA gene sequences, discriminated by BfaI restriction enzyme treatment, is promising. Patients sometimes show a moderate peripheral leucocytosis. The pleomorphic filamentous bacteria may be stained in peripheral blood leucocytes or tissue samples using Gram’s, Wright’s, or silver stains. In cases of streptobacillary septic arthritis, the synovial fluid contains many leucocytes (neutrophils around 50 000 × 109/litre) and bacteria may be visible. False-positive serological tests for syphilis (Venereal Disease Research Laboratory (VDRL) test) are found in 15 to 25% of cases.
S. moniliformis is sensitive to penicillin and can be treated with benzyl penicillin 1.2 million units/day for 5 to 7 days followed by oral penicillin or ampicillin 500 mg four times a day for 7 days if there is improvement. Procaine benzylpenicillin (adult dose 600 mg or 600 000 units) by intramuscular injection every 12 h for 7 to 14 days and penicillin V 2 g/day by mouth are also effective. Penicillin-resistant L-variants are susceptible to streptomycin (7.5 mg/kg intramuscularly twice daily), tetracycline (500 mg orally four times a day), and probably erythromycin. For patients hypersensitive to penicillin, erythromycin, chloramphenicol, tetracycline, or cephalosporins can be used. Erythromycin was used successfully in the boarding-school outbreak of Haverhill fever in England in 1983.
Patients with endocarditis should be treated with intravenous benzylpenicillin, 4.8 to 14.4 g (8–24 000 000 units) each day for between 4 and 6 weeks, or 4.8 000 000 units of procaine benzylpenicillin daily by intramuscular injection for 4 weeks if the cultured organism has a sensitivity of 0.1 µg/ml. The addition of streptomycin improves bactericidal activity and eliminates L-forms.
Affected joints may require aspiration or even surgical debridement.
The untreated case fatality was reported to be 10 to 13%. However, the overall mortality in patients with endocarditis, many of whom were untreated or treated late, exceeded 50%. Fulminant and rapidly fatal cases have been reported in immunocompetent children and adults. In survivors, residual arthralgia persisting for as long as 10 years has been described.
Spirillum minus infection (sodoku, sokosha)
The cause of sodoku, Spirillum minus, is a relatively thick tightly coiled Gram-negative rod or spirillum (not a spirochaete), between 2.5 and 5.0 µm long, with 2 to 6 (commonly 3) spirals, resembling campylobacters. It darts about under the power of its terminal flagella. Continuous culture on artificial media has not been achieved, but the organism can be demonstrated by inoculating material from the bite wound, regional lymph nodes, or blood intraperitoneally into mice or guinea pigs. Organisms usually appear in the rodent’s blood within 5 to 15 days of inoculation. Spirillum minus may be found in the blood of up to 25% of apparently healthy rodents and in the eye discharge and mouths of rats with interstitial keratitis and conjunctivitis. In the 1930s, ‘sodoku inoculata’ (the blood of infected guinea pigs) was used to treat neurosyphilis.
Sodoku is found worldwide but is particularly common in Japan. In Asia it is commoner than S. moniliformis as a cause of rat-bite fever. Infection results from bites, scratches, or mere contact with rodents or their predators including dogs, cats, and pigs.
The initial bite wound usually heals without signs of local inflammation. After an incubation period of 1 to 36 days, but usually 14 to 18 days, there is sudden fever which, in untreated cases, reaches its height in 3 days and resolves by crisis after a further 3 days. At the start of the illness the healed bite wound becomes inflamed, swollen, and indurated; it may break down to become a necrotic or suppurating ulcer. Regional lymph nodes are usually enlarged and tender. Other acute symptoms include rigors, myalgia, and prostration. A rash develops in approximately one-half of patients. It often spreads from the site of the bite and consists of angry purplish or reddish-brown indurated papules, plaques, or macules with urticarial lesions. Arthralgia may be severe but there are no joint effusions. Severe manifestations including meningitis, cerebral abscess, encephalitis, endocarditis, myocarditis, myocardial abscess, pleural effusion, chorioamnionitis, subcutaneous abscesses, and involvement of liver, kidney, and other organs are seen in about 10% of patients. Relapses of fever, rash, and other symptoms lasting 3 to 6 days may occur between remissions of between a week and 2 months and occasionally up to a year in untreated patients.
Sodoku must be distinguishable from streptobacillary rat-bite fever (see above). Its tendency to relapse may suggest relapsing fever (Borrelia spp.) or trench fever (Bartonella quintana).
The diagnosis can be confirmed by examining aspirates from the bite wound, lymph nodes, exanthem, or blood (thick and thin films) using dark-field microscopy or Wright’s or Giemsa’s stains. The organism can be detected in the blood, peritoneal fluid, or heart muscle of inoculated rodents but cannot be cultured on artificial media. No specific serological tests are available. False-positive serological tests for syphilis are found in 50 to 60% of cases, and reactions with Proteus OXK are also common.
Penicillin is the drug of choice. For adults, procaine benzylpenicillin 600 mg (600 000 units) should be given every 12 h for 7 to 14 days. Penicillin V, 2 g/day by mouth, is also said to be effective. A Jarisch–Herxheimer reaction may complicate penicillin treatment.
Prevention of rat-bite fevers
These infections can be prevented by controlling wild peridomestic rodents and by encouraging laboratory and pet shop workers to wear protective gloves and to handle rodents carefully, to avoid hand-to-mouth or hand-to-eye contact, to wash their hands, and to clean all rodent bite wounds. The efficacy of postexposure prophylaxis with antibiotics is unproven. Young children should be supervised when they handle pet rodents to avoid bites, kissing, sharing food, and hand-to-mouth or hand-to-eye contact. An enzyme-linked immunosorbent assay (ELISA) has been developed for surveillance of rodent colonies for S. moniliformis. Haverhill fever is prevented by avoiding the consumption of raw milk, by monitoring water supplies (especially those not derived from the mains), and by controlling rat populations.
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