SIGNIFICANT ZOONOTIC DISEASE OF NON-HUMAN PRIMATES November 1988 Division of Veterinary Medicine Walter Reed Army Institute Washington DC 20307 Significant Diseases of Nonhuman Primates TABLE OF CONTENTS Herpes-B ..................................................... 3 Measles ...................................................... 5 Rabies ...................................................... 6 Tuberculosis ................................................. 7 Salmonellosis ................................................ 8 Shigellosis .................................................. 9 Amebiasis ................................................... 11 Balatidiasis ................................................ 12 Giardiasis .................................................. 13 Helminths ................................................... 13 Bites & Scratches ........................................... 14 Allergic Sensitivities ...................................... 14 Arthropod Infectations ...................................... 15 Herpes B (Herpesvirus simiae) AGENT: DNA Herpesvirus. There are more than 35 herpesviruses of nhps most of which are not zoonotic. This disease has been described as one of the most feared infections of non-human primate handlers. First reported case of encephalitis caused by B virus in monkey handler was in 1932. Called B virus after the initials W.B. of the first patient. 23 additional cases described through 1973. Four cases including first known person to person transmission occurred in Pensacola Fla in 1987. Most of these cases resulted in encephalitis and 20 resulted in fatalities. In 1988 two confirmed cases occured. Both were identified early and clinical signs were averted by administration of Acyclovir. RESERVOIR AND INCIDENCE: The virus is enzootic in rhesus, cyno and other asiatic monkeys of macaque genus. Baboons, Chimpanzees, and African Greens have also shown positive titers. Young monkeys can be infected by adult carriers as soon as they lose maternal antibody. One study found that 80% of adult monkeys in a closed colony had been infected . The virus has been isolated from trigeminal and lumbosacral ganglia in clinically normal seropositive rhesus and cyno's. TRANSMISSION: Basically by direct contact. Transmission to man is thought to occur via bites, scratches, aerosols, or improper handling of contaminated monkey tissues. Virus has been isolated from saliva, blood, urine, feces, and kidney tissue cultures of infected monkeys. Most cases have occurred in people exposed to monkeys or monkey tissues. One case occured by common use of an over-the-counter antibiotic oinment passing the virus from an infected individual to another person. An additional case occurred by self innoculation of a needle, after the needle had been use for blood colleciton. The virus has been isolated from animals that had no visible lesions. AN INFECTED MONKEY SHOULD BE CONSIDERED INFECTED FOR LIFE. DISEASE IN NONHUMAN PRIMATES: The animal may be completely asymptomatic. The virus may cause mild cold sore type lesions of mucous membranes, dorsum of the tongue, lips or face; similar to those caused by Herpes simplex in man. These usually heal spontaneously in 7 to 14 days. There may be mild conjunctivitis and nasal discharge als present. In some animals the disease may be severe and cause considerable discomfort as well as neurologic signs and symptoms. The virus remains latent and may reactivate spontaneously or in ties of stress resulting in virus shedding. An animal should be considered to be infected for life. AN INFECTED ANIMAL CAN APPEAR NORMAL! DISEASE IN MAN: The disease has been characterized by a variety of symptoms which generally occur within a month of exposure. Symptoms have included vesicular skin lesions at or near the site of inoculation, localized neurologic symptoms, ascending paralysis, and ultimately encephalitis. Death usually occurs 3 to 21 days after the appearance of clinical signs. A unique feature of the Pennsacola cases was the occurrence of mild disease in 2 of 4 patients. Both of these received Acyclovir early in the course of the disease. They became culture negative and lesions resolved during therapy. Since there is a high percentage of infection in monkeys yet relatively few human cases, risk of acquiring infection appears to be low. Possible reasons for this apparently low rate of transmission may include: 1. Infrequent virus shedding by macaques. 2. Cross reactive immunity stimulated by Herpes simplex infection or Herpes zoster (chicken pox). 3. Undetected asymptomatic infection in man. The frequency of this has not yet been adequately assessed but antibody titers have been found in some monkey handlers showing no signs of disease. In a retrospective study of 95 banked sera from monkey handlers at NIH, 3% were found to be seropositive, with no history of a bite. NIH is currently conducting a prospective study of monkey handlers to determine incidence of antibody specific for Herpes B. DIAGNOSIS: Diagnosis is by histology, virus culture, and serology. TREATMENT: Anti viral therapy with Acyclovir (9-[2-hydroxyethoxymethyl] guanine), both in vivo and in vitro efficacy against B-virus has been demonstrated. Hyperimmune human B-virus globulin or vaccine is not currently available. These are from the guidelines established by the B-Virus Working Group, June 1987: 1. Macaques should be used for research only when clearly indicated. 2. B virus - free animals should be used whenever possible and maintained under conditions to assure maintenance of this status. 3. Direct handling of macaques should be minimized and appropriate restraint methods employed (ie, squeeze cages, chemical restraint, pole and collar etc.). 4. Protective clothing should be worn when working with macaques or macaque tissues (long sleeves, gloves, mask, goggles). 5. Cages and equipment should be maintained free of sharp edges that could cause injuries. 6. Access to areas where macaques are housed should be limited. 7. Routine screening of animals for B virus is NOT recommended. 8. Animals with lesions should be quarantined until lesions have healed. 9. Education and training of personnel should be assured. 10. An occupational medical service should be available a. Employee serum samples collected and banked annually). b. All bite or scratch wounds should be immediately and thoroughly scrubbed with soap and water ( or Modified Dakin's solution: buffered sodium hypochlorite 0.5%) Refer for medical treatment if necessary. c. All bite or scratch wounds should be reported, documented, and followed up for one month. MEASLES Rubeola Virus AGENT: Paramyxovirus RESERVOIR AND INCIDENCE: Reservoir appears to be the human population. New world monkeys are more resistant than old world monkeys but exhibit high mortality when infected. TRANSMISSION: Virus is excreted from the mucous membranes of the eye and pharynx and later from the respiratory and urinary tracts. Virus is shed in the prodromal phase and continues through the exanthematous phase. Highly contagious. It can spread from man to monkey, man to man, and monkey to man. DISEASE IN NONHUMAN PRIMATES: Signs include rash, fever, facial edema, giant cell pneumonia, conjunctivitis, nasal discharge. DISEASE IN MAN: The incubation period is 9-11 days. Signs include conjunctivitis, Koplick spots - bluish white spots on buccal mucosa 2-3 days after onset, leucopenia, rash in mouth, cheeks, neck, chest, and body. Can be complicated by middle ear infection, bronchopneumonia, encephalitis. There is fetal risk if contracted during pregnancy. DIAGNOSIS: clinical signs, serology, histopath PREVENTION/CONTROL: Vaccinate personnel working with nonhuman primates (Live attenuated measles vaccine) if they do not have: 1. A titer to rubeola (HI >1: 4 protective) 2. Confirmed history of previous vaccination 3. Confirmed prior disease Consider vaccination of susceptible populations of nonhuman primates (>6 months of age) where contact with humans cannot be adequately controlled. (Live attenuated measles vaccineAttenuvax) RABIES Hydrophobia, Lyssa AGENT: Rhabdovirus which causes an acute almost invariably fatal disease. RESERVOIR AND INCIDENCE: Worldwide distribution (few countries are exceptions). Primary reservoirs vary geographically, eg. foxes, bats, raccoons, skunks, dogs, cats, cattle, and others. 16 cases have been confirmed in nonhuman primates, including chimpanzees, cebus, cynos, and squirrel monkeys. All source countries of NHP's have endemic rabies. TRANSMISSION: Virus laden saliva via bite, scratch, or abrasion. Tissues and fluids in the laboratory. Rabid animals may shed virus in saliva 1-14 days before showing signs. DISEASE IN MAN: Incubation: 14-60 days (Range 10 days to over 1 year) Asymptomatic during this phase. Prodromal: Fever, headache, malaise, fatigue, anorexia. May be a paresthesia at the bite wound site. Acute Neurologic Phase: Hyperactivity, bizarre behavior interspersed with periods of normal cooperative behavior. Coma: Gradual paralysis with coma and respiratory arrest. Death or Recovery: Recovery rare and reported in only 3 cases of human rabies. In each case, prophylaxis was begun before the onset of clinical illness. DIAGNOSIS: Consider Rabies as a possible problem in any wild caught or random- source laboratory animal of unknown vaccination history showing central nervous system signs or symptoms. Virus isolation from body fluid or tissue. Fluorescent antibody (FA) staining of tissues, including cornea, frozen skin, mucosal scrapings, as well as brain. PREVENTION/CONTROL: The virus is destroyed rapidly at greater than 50oC and survives no more than a few hours at room temperature (Can persist for years in frozen tissues). Vigorous first aid for bite wounds. Consult Health Authority if suspected exposure. Discourage keeping of wild animals as pets. Discourage the vaccination of wild animal pets for rabies. A modified live or attenuated vaccine may produce disease and the efficacy of a killed vaccine is not known. Pre-immunize high risk personnel for rabies - HDCV is now available (Human Diploid Cell Vaccine). Titers should be checked routinely and boosters given as needed. TUBERCULOSIS AGENT: TB is caused by the gram positive, acid fast, aerobic, bacillus of the Mycobacterium genera. RESERVOIR AND INCIDENCE: The three most common species of mycobacteria are: 1. M. bovis (cattle, dogs, swine, nonhuman primates) 2. M. avium (birds, swine, sheep, nonhuman primates) 3. M. tuberculosis (man, nonhuman primates, cattle, dogs, swine, psitticines). The incidence of human TB has decreased dramatically in the past several decades due to the Bovine Test and Eradication Program. and the availability of effective therapy. TB does still occur sporadically in humans in the US and other countries. All three types are capable of causing disease in man although M. tuberculosis (variety hominis) is by far the most common. Nonhuman primates can carry all three types but most infections are caused by M. tuberculosis variety hominis. While most nonhuman primates are capable of contracting TB, Old World species appear to be more susceptible to the disease than New World species and great apes. Most cases of TB in monkeys are thought to arise from human contact. Animals may be imported from areas of the world where the incidence of the disease is high and where contact between humans and simians is frequent. In close confinement the disease can spread rapidly. TRANSMISSION: Mycobacterium bacilli are transmitted from infected animals or infected tissue primarily via the aerosol route. May also be contracted via ingestion or cutaneous inoculation of the bacilli. Personnel caring for infected animals as well as those performing necropsies on infected animals are at risk for contracting the disease. Exposure to dusty bedding of infected animals, coughing of infected animals, and aerosolization of the organism during sanitation procedures may also be sources of the disease in the lab environment. Once within the body the organism may spread throughout the lungs, lymphatics, blood vascular system, and many visceral organs. DISEASE IN NONHUMAN PRIMATES: The signs of TB may be insidious with only slight behavioral changes noticed, followed by anorexia and lethargy. Often animals die suddenly while appearing to be in good condition. Other signs which might be seen include diarrhea, suppuration of lymph nodes, ulceration of the skin, and palpable splenomegaly and hepatomegaly. The organ of predilection is the lung but lesions may also be seen in the pleura, intestines, lymph nodes, liver, kidney, spleen, and peritoneum. Under the surface of these tissues are yellowish white to gray nodules filled with caseous material which may rupture and produce cavitation. Although skeletal involvement in primates is rare, tuberculosis of the spine may cause paralysis of the hind limbs (Potts disease). DISEASE IN MAN: In humans the clinical signs depend on the organ system involved. The most familiar signs related to pulmonary TB are cough, sputum production, and hemoptysis. The patient may be asymptomatic for years. General signs may include anorexia, weight loss, lassitude, fatigue, fever, chills and cachexia. TB may affect virtually every other organ system with signs or symptoms relating to the individual system. Miliary TB is most often seen in the very young and o]d people. DIAGNOSIS: The diagnosis of TB is often difficult. Three tests are commonly used for presumptive diagnosis: 1. Intradermal TB test - Mammalian Tuberculin 2. Radiography 3. Acid fast stained sputum smear Confirmation by culture, histopathology, or animal inoculation. PREVENTION/CONTROL: Multifaceted and includes: 1) Personnel education 2) Wearing of protective clothing when handling nonhuman primates 3) A regular health surveillance program for humans and nonhuman primates 4) Isolation and quarantine of suspect animals 5) Rapid euthanasia and careful disposal of infected animals. 6) Vaccine: A vaccine, BCG, is available (Bacille Calmette-Guerin, strain of M. Bovis) It is used in humans quite often in G. Britain, in high risk groups. It is effective, but it causes the patient to have a positive TB test. All Personnel working with NHP's who convert to a positive skin test should be referred for appropriate medical treatment and follow up and should not work with animals until shown to be non infectious. SALMONELLOSIS AGENT: Gram negative bacteria. Out of 1600 recognized serotypes of Salmonella, S. typhimurium & S. enteritidis have been associated most commonly with lab animal colony infections. RESERVOIR AND INCIDENCE: The organism inhabits the intestinal tract of many animals including birds and laboratory animals (rats, mice, hamsters, guinea pigs, nonhuman primates) and humans. Salmonella occurs worldwide. The house mouse may also be a reservoir of the infection and may play a role in human and animal salmonellosis. Humans and animals may be carriers and asymptomatic shedders of the organism. Salmonella carriers in newly imported Rhesus and Cynomolgus monkeys exceeded 20% in some shipments. Indirect transmission via contaminated food and water are the most common sources but transmission may also be by direct contact. It is a common contaminant of sewage. Found in many environmental water sources. Environmental contamination continues to be a potential source of infection for lab animals and secondarily for personnel handling those animals. Animal feed containing animal by products continues to be a source of Salmonella contamination, especially if the diets consist of raw meal and have not undergone the pelleting process. DISEASE IN ANIMALS: Can be asymptomatic with clinical signs precipitated by stress; epizootic enteritis, septicemia and variable mortality. High percentage of survivors become carriers. DISEASE IN MAN: Acute gastroenteritis with sudden onset of abdominal pain, diarrhea, nausea, and fever. May lead to septicemia. May be an inapparent infection. DIAGNOSIS: Fecal Culture with selective media. In the carrier state bacterium resides in the gall bladder (NHP). SHIGELLOSIS AGENT: Gram negative, non spore forming, bacillus. S. flexneri (types 2, 4, 6), S. sonnei, and S. dysenteriae are the most common organisms causing problems in NHP. S. sonnei is the most common isolate in man. A significant zoonotic disease that has frequently been transmitted from non-human primates to man. RESERVOIR AND INCIDENCE: Shigella is one of the most commonly identified causes of diarrhea in NHP. Humans are the main reservoir. TRANSMISSION: Fecal oral route, i.e. contaminated food or water, or by direct contact, aerosol, or mechanical vectors such as flies. The organism is shed from clinically ill as well as asymptomatic humans and NHP. Only minimal contact is necessary for transmission. DISEASE IN NONHUMAN PRIMATES: A subclinical carrier state is common and overt disease may be precipitated by stress. Signs include watery to bloody diarrhea, weakness, and edema of the face and neck. Rectal prolapse is common. High mortality can result from Shigellosis in NHP. Recovered animals often are carriers and serve as a reservoir of infection. Post mortem lesions include ulcerative colitis, distended hyperemic large intestine with mucus and blood in lumen, and enlarged mesenteric lymph nodes. DISEASE IN MAN: Signs range from none to a severe dysentery syndrome with blood and mucus in the feces, abdominal cramping, tenesmus, weight loss, and anorexia and diarrhea. (More commonly a mild diarrhea). Disease is much more severe in children than in adults and has resulted in fatalities in children who contacted diseased pet or zoo monkeys. Carrier state may persist in recovered individuals. DIAGNOSIS: Definitive diagnosis requires isolation of Shigella sp. from fresh rectal swabs, using selective media. Consider Shigella if human or NHP develops acute diarrhea, especially if blood or mucus is present. TREATMENT: Fluids, electrolytes, and antibacterials. PREVENTION\CONTROL: Prevention is aimed at improving sanitation and personal hygiene. Care must be taken not to contaminate food, water, or clothing with fecal material. Protective clothing should be worn when working with nonhuman primates. Stressing of animals should be avoided. Sick animals should be isolated. A quarantine period to evaluate the health of newly received primates is essential. However, a quarantine period does not guarantee an animal to be free of Shigella. Since bacterial isolation is often difficult it is best to assume that all nonhuman primates are potential shedders of the organism. Vaccines have not proven to be successful. Minimize human traffic through primate colonies. AMEBIASIS AGENT: Entamoeba histolytica. RESERVOIR AND INCIDENCE: Worldwide in humans with greater prevalence in tropical areas. Reported incidence of 0-31% in the feces of clinically normal Rhesus monkeys, 2-67% in Chimps, and up to 30% in other NHP. TRANSMISSION: Transmission may be by ingestion of infective cysts, contaminated water or food, by flies, or fomites. Exists as resistant cysts or more fragile trophozoites. CYSTS are the INFECTIOUS form found in the stool of asymptomatic carriers or patients with mild disease. The cysts remain viable, if moist and cool for 12 days. Remain viable for 30 days in water. Laboratory animal personnel are usually infected from fecal matter transferred to the skin or clothing. DISEASE: Most humans have few or no detectable symptoms. May show amebic colitis when trophozoites invade the bowel. Mild watery diarrhea to acute fulminating bloody or mucoid dysentery with fever and chills. Disease may have periods of remission and exacerbation over months to years. Rarely liver, lung, & CNS, amebic abscesses may form. DIAGNOSIS: Use fresh fecal specimen to identify cysts or trophozoites. Sedimentation. Must measure to distinguish from other nonpathogenic amoeba. TREATMENT: Metronidazole PREVENTION/CONTROL: Strict sanitation & personal hygiene, protective clothing and gloves. Fecal screening of NHP. Protect water supply from fecal contamination. Usual chlorine levels don't destroy cysts. 1Oppm chlorine residual necessary to destroy cysts Heat to 50oC kills cysts. BALANTIDIASIS AGENT: Large ciliated protozoan, Balantidium coli. Trophozoite. 50-70 microns by 40-50 microns. RESERVOIR AND INCIDENCE: Distributed worldwide. Common in swine. Humans, great apes, & several monkey species may carry it. Incidence in NHP colonies - 0 to 63%. Usually asymptomatic, but may see diarrhea. TRANSMISSION: Ingestion of cysts or trophozoites from infected animal or human feces. Cyst is the infectious form. Contaminated water or food. DISEASE IN ANIMAlS AND MAN: Ulcerative colitis. Diarrhea or dysentery. Nausea, vomiting. Abdominal pain. Severe cases, may see blood &/or mucus in stool. Often see asymptomatic infections in humans DIAGNOSIS: Use fresh fecal samples to identify trophozoites or cysts. TREATMENT: Tetracycline, metronidazole, paromomycin, ampicillin PREVENTION/CONTROL: Good sanitation & personal hygiene practices in NHP & Swine colonies. Protect water & food from fecal contamination. Identify positive lab animals and treat. GIARDIASIS AGENT: Giardia duodenalis - man, rodents, birds, & reptiles. This is the only zoonotic type. Dogs and NHP's represent the greatest public health risk. This is the most common intestinal parasite of people in the U.S. RESERVOIR AND INCIDENCE: Worldwide in distribution, occurs among all vertebrates and many lab animal species including dogs and NHP's. TRANSMISSION: Contamination of water by beavers, dogs, & humans. NHP's can also be a source. Infective cysts are ingested. Only a few cysts can cause severe disease. Asymptomatic hosts can shed organism intermittently. Shown in children to be transmitted via fecal contamination of fingers, toys, and the environment. DISEASE IN ANIMALS: Usually asymptomatic although may produce diarrhea. DISEASE IN MAN: Chronic intermittent diarrhea, steatorrhea, malaise, anorexia, and weight loss. The stool is frequently mucus laden, light colored and soft, not watery. More severe infections in young or immunocompromised DIAGNOSIS: FRESH feces (not more than 5 to 10 minutes old) to detect trophozoites or cysts. TREATMENT: Metronidazole (FLAGYL) PREVENTION/CONTROL: Fecals to screen dogs and NHP's. Water supplies monitored. Hygiene, protective clothing, when handling animals. HELMINTH INFECTIONS Many of the helminth parasites common to both animals and humans have an indirect life cycle that is interrupted in the laboratory environment and thus limits the zoonotic potential of these organisms. Laboratory housed primates are the most likely source of parasitic infection for animal handlers. Helminths are POTENTIALLY Zoonotic in the laboratory environment, but they represent a significantly smaller problem than bacterial or viral diseases. Exceptions are those with a direct life cycle. GENERAL: Proper quarantine, surveillance and treatment to decrease endoparasitic burden, routine sanitation to eliminate parasitic ova before they can become infective, and education of personnel on standard hygiene practices are measures that can be taken to prevent transmission of these diseases. BITES AND SCRATCHES Bites cause pain, anxiety, wound disfigurement, and wound infections. Many organisms are capable of infecting animal bite wounds including Pasteurella spp., DF-2, Clostridium tetani, Streptobacillus moniliformus, and Spirillum minus. ALLERGIC SENSITIVITIES Allergic skin and respiratory reactions are quite common in personnel working with laboratory animals. Many animals are implicated including the cat, dog, horse, rabbit, rat, mouse, hamster, gerbil, guinea pig, and NHP. Hypersensitivity reactions include: 1. Nasal congestion 2. Runny nose 3. Sneezing 4. Itching of eyes 5. Angioedema 6. Asthma 7. A variety of skin manifestations (Localized urticaria and eczema) THE MAJOR URINARY PROTEIN COMPLEX IS ONE OF THE MOST RECENT ALLERGENS TO BE IDENTIFIED FROM MOUSE PELTS AND SKIN. Suggests that a possible cause of sensitization in lab personnel is dispersal of urinary protein from litter in mouse cages. TREATMENT AND PREVENTION: 1. Pharmacologic treatment 2. Allergen Immunotherapy 3. Complete avoidance of the antigen 4. Reducing exposure to offending antigen a. Reduction of direct animal contact time b. Increasing room ventilation c. Exhaust hoods d. Filter caps on cages e. Protective clothing, masks, and respirators. ARTHROPOD INFESTATIONS Several arthropod infestations in man have been documented following direct contact with infected animals including pediculosis from a spider monkey and mange; Sarcoptes scabei from an old world primate, and Fonsecalges saimirii from a squirrel monkey. Other health hazards to humans due to ectoparasitic infestations from arthropods associated with laboratory animals are most often mild and limited to ALLERGIC DERMATITIS. PREVENTION/CONTROL: Fleas, ticks, and mites should be controlled. Gloves and protective clothing should be worn when handling lab animals.