Spirochetes/Rickettsia 8/23/07 A scene like this may seem very pleasant. But I’m going to point out dangers. Here’s why: You can’t depend on finding . . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 You won’t find many trees with warnng signs . . . But you may face ticks ahead of you in the woods. And those ticks may threaten you with Rocky Mountain Spotted Fever . . . and many other diseases Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Because of the threat of tickborne disease, I might call this lecture . . . Marvin J. Bittner MD

Rickettsia Group of bacteria that are fastidious, obligate intracellular pathogens They are pleomorphic & coccobacillary • The organisms will not show up on Gram stain, but can be seen when either Gimenez or Giemsa stains are used

Why Rocky Mountain Spotted Fever? Spirochetes/Rickettsia 8/23/07 Why Rocky Mountain Spotted Fever? Prototype rickettsiosis Main reason for deaths? You may wonder why I am putting special emphasis on Rocky Mountain Spotted Fever. There are two reasons: First, Rocky Mountain Spotted Fever is the prototype rickettsiois. You can guess that from the name of its causative organism: Rickettsia rickettsiae. Second, do you know what the main reaon is for deaths in Rocky Mountain Spotted Fever? Marvin J. Bittner MD

Etiology: Invertebrates Spirochetes/Rickettsia 8/23/07 Etiology: Invertebrates 1. Rickettsia rickettsiae 2. Ticks (tolerate infection) Dermacentor andersonii, D. variabilis (“hard”) Transstadial, transovarial transmission Dermacentor andersonii, which is the western wood tick, or Dermacentor variabiliilis, the dog tick larva to nymph to adult Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Etiology Microbe R. rickettsii Vector Tick Reservoir Rodents Host Intruder . . . of Rocky Mountain Spotted Fever: The microbe Rickettsia rickettsii is transmitted by a tick vector from its rodent reservoir to human intruders into the wildlife cycle. We become dead-end hosts. What is the epidemiology of Rocky Mountain Spotted Fever? Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Person Outdoor activity Peak age 5-9 Mortality highest in elderly . . . to get Rocky Mountain Spotted Fever is one who engages in outdoor activity. That’s because of tick exposure. The peak years are ages 5 to 9. That’s old enough to be active outdoors but a bit too young to pay a lot of attention to tick bites. Even though the disease is particularly common in children, mortality is highest in those 70 and older: 11.5%. Marvin J. Bittner MD

Development of illness Spirochetes/Rickettsia 8/23/07 Development of illness Inoculation Rickettsemia Endothelial localization Vasculitis The illness develops following inoculation of Rickettsia rickettsii via s tick bite. A rickettsemia develops as the microbes travel through the blood vessels. Eventually they localize in the endothelium of the blood vessels. A vasculitis ensues. It accounts for many of the manifestations of the disease. You recognize Rocky Mountain Spotted Fever . . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Clinical recognition Rash Fever Headache Other . . . by the triad of rash, fever, and headache. Early in the illness, rash may not be present. So, when you seen a patient who might have had tick exposure and who comes to you with rash and fever, one of your considerations is Rocky Mountain Spotted Fever. In addition to rash, fever, and headache, often there may be other manifestations. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 RMSF rash on hands . . . Seen first on hands . . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 . . . And feet. Then . . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 . . . It spreads toward the center of the body. So-called centripetal spread. This centipetal spread is also seen in atypical measles. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 These pictures show children. That makes sense since the peak age group is 5 to 9 years old. The rash develops from the vasculitis, which causes blood to leak from damaged vessels. Initially pinpoint red lesions are seen in the distal extremities, including the palms and soles. Relatively few other diseases cause rashes in the palms and soles. They include syphilis, measles, and infective endocarditis. Because the rash reflects bleeding, at times. . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 the bleeding may be extensive enough to produce a blood-filled blister or bulla. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Sometimes the rash may be hard to discern. Of course, at times the patient may start to feel sick and appear in the office before the rash appears on the patient. So there may be delay in diagnosis. The reason for deaths in Rocky Mountain Spotted Fever is not delay in . . . Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Fever and headache Fever 102 to 105 degrees 2 to 3 weeks without treatment Headache: severe We also see fever to 102 to 105 degrees. It persists 2 to 3 weeks without treatment. The headache may be severe. Other problems may also occur. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Clinical recognition Rash Fever Headache Other In addition to rash, fever, and headache, you may see chills, myalgias and serious complications. Activation of the clotting system may result in disseminated intravascular coagulation. Neurologic complications and even death may ensue. Mortality was 30% in the pre-antibiotic era. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Clinical recognition Rash Fever Headache Other rash, fever, and headache. . . perhaps with other problems. Remember that rash may sometimes be absent, especially early in the illness. Now that I’ve talked about etiology, epidemiology, and clinical picture, I’ll look at how you confirm the diagnosis in the laboratory. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Laboratory diagnosis Skin biopsy: immunofluorescent stain Serology Weil-Felix archaic Immunofluorescent antibody No growth on routine culture If you do a skin biopsy, you can make a diagnosis in a day or so. Some people don’t bother to do a biopsy. Although the biopsy is 100% specific, it sometimes gives dangerous false negative reports. Later, you can confirm your diagnosis by doing tests for antibodies, or serology. The old tests, the Weil-Felix tests, are now archaic. Laboratories now have immunofluorescent antibody, or IFA, assays. The problem is that you have to wait a couple weeks before you can expect the antibodies to develop and draw the blood for the convaslescent titers. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 . . . and under UV light, it glows. Tetracyclines can cause tooth staining in children under the age of 9. So ordinarily, we steer clear of doxycycline. But the risk of tooth staining is small for s single course of treatment for Rocky Mountain Spotted Fever. How can we prevent Rocky Mountain Spotted Fever? Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Prevention Vector control impractical Vaccine unavailable So . . . caution outdoors Long clothing Skin inspection What about prevention through vector control? In other words, get rid of the ticks from the woods. This is impractical. Neither has a vaccine been successful. The mainstay of prevention if caution outdoors. Long clothing makes it harder for ticks to find skin. Skin inspection for ticks, espcially with children, is important, since tick bites may be painless. Let’s summarize the key facts about Rocky Mountain Spotted Fever: Marvin J. Bittner MD

Rocky Mountain Spotted Fever Spirochetes/Rickettsia 8/23/07 Rocky Mountain Spotted Fever Physician suspicion crucial R. rickettsii, ticks Not just Rockies Vasculitis Rash, fever, headache Doxycycline, look for ticks Physician suspicion is crucial in making a prompt diagnosis. Rickettsia rickettsii is the causative organism, transmitted by ticks from a wild vertebrate reservoir to humans who intrude into the wildlife cycle and become dead-end hosts. Despite the name, Rocky Mountain Spotted Fever is more common in the Southeast and Oklahoma than it is in the Rockies. But its distribution is widespread, even including New York City. The disease develops because of damage to blood vessels, a vasculitis. The key findings are rash, fever, and headache. But rash may be absent, especially early in the disease. The drug of choice is doxycycline, even in children. Looking for ticks after outdoor exposure is the most important prevention measure. Marvin J. Bittner MD

Rickettsiae & spirochetes Rocky Mountain Spotted Fever Rickettsial biology Other rickettsioses Spirochetes

Spirochetes/Rickettsia 8/23/07 Order Rickettsiales Family Rickettsiaceae Tribe Rickettsiae Genus Rickettsia Genus Coxiella Genus Rochalimaea Family Bartonellaceae Another player, the family Bartonellaceae, which includes Bartonella bacilliformis, the cause of Bartonellosis, is shaking up this classification. Marvin J. Bittner MD

Spotted Fever Group • Rocky Mountain spotted fever – Rickettsia rickettsii • Rickettsial pox – Rickettsia akari • Canadian typhus – Rickettsia canada • Mediterranean spotted fever – Rickettsia conorii • Siberian tick typhus – Rickettsia siberica • Queensland tick typhus – Rickettsia australis Murine typhus (also known as endemic typhus and fleaborne typhus) – Rickettsia mooseri (typhi) • Epidemic typhus (also known as Brill- Zinsser disease and louseborne typhus) – Rickettsia prowazekii • Scrub typhus (or Chigger fever) – Rickettsia tsutsugamushi

Spirochetes/Rickettsia 8/23/07 Rickettsial groups Spotted fever group Rocky Mountain Spotted Fever Other spotted fevers Rickettsialpox Typhus group Epidemic typhus, Brill-Zinsser Murine, scrub typhus The genus Rickettsia is left with two groups of organisms. This grouping is based on the clinical diseases that they cause. Rocky Mountain Spotted Fever is the prototype of the spotted fever group. But there are other similar spotted fevers occurring in other parts of the world. Also, there is rickettsialpox, which often occurs in an urban environment. The prototype of the typhus group is epidemic typhus. Please don’t confuse epidemic typhus, which is spread to humans by licein conditions of poor hygiene, with typhoid fever, which is caused by Salmonella and generally transmitted by contaminated food. Do you know about Anne Frank, theJewish girl who wrote a diary about her life in Amsterdam in World War II before she was taken by the Nazis to the concentration camps? Anne Frank died of epidemic typhus. Humans are not dead-end hosts for epidemic typhus. Other disiseases in this group include the recurrent form of typhus, called Brill-Zinsser disease, murine typhus, and scrub typhus, scrub typhus being caused by Rickettsia tsutsugamushi. Marvin J. Bittner MD

Typical rickettsial illness Spirochetes/Rickettsia 8/23/07 Typical rickettsial illness Inoculation eschar (exception: Rocky Mountain Spotted Fever) Rickettsemia Endothelial growth Vasculitis 1-2 week incubation Rash, fever, headache What is the pathogenesis of a typical rickettsial illness? At the site of inoculation, an eschar develops. Rocky Mountain Spotted Fever is an exception to this. Otherwise, Rocky Mountain Spotted Fever shows the typical pattern of rickettsemia, endothelial growth, vasculitis, and, after 1 to 2 weeks of incubation, the onset of rash, fever, and headache. However, most rickettsial rashes, unlike Rocky Mountain Spotted Fever, start at the trunk and move outward. Marvin J. Bittner MD

Rickettsial diagnosis Spirochetes/Rickettsia 8/23/07 Rickettsial diagnosis Must suspect clinically Immunoflorescent stained skin biopsy Weil-Felix passé Serology usually (but delay in getting results) Isolation hazardous Rule out others . . . almost always must be made clinically. Clinical suspicion drives you to order an immunostained skin biopsy. The Weil-Felix serology is now passé. Other serological tests have replaced it. Isolation of rickettsiae in the laboratory is hazardous. The usual approach is to suspect a rickettsial disease and rule out simialr diseases. For example, if meningococcal meningitis is also suspected, you might do a lumbar puncture to exclude it. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Rickettsial control Public health Reporting Vector/reservoir No vaccines Prevention and control measures focus on public health. This means reporting cases and sometimes controlling the vector or reservoir, or at least minimizing exposure. Vaccines are generally unavailable. Marvin J. Bittner MD

Rickettsial diseases other than Rocky Mountain Spotted Fever Spirochetes/Rickettsia 8/23/07 Rickettsial diseases other than Rocky Mountain Spotted Fever Other spotted fevers (in other parts of world) Rickettsialpox (urban, from mice and mites) Typhus group (epidemic typhus from lice) Here’s what to remember about the other rickettsial diseases. In other parts of the world, there are other spotted fevers that rsemble Rocky Mountain Spotted Fever. Rickettsialpox has an urban distribution, a mouse reservoir, and a mite vector. The prototype of the typhus group is the disease that killed Anne Frank, epidemic typhus, caused by Rickettsia prowazekii. Its reservoir is humans and flying squirrels, in other words, Rocky and his Friends. It is transmitted by lice, typically when you inhale louse feces that are made airborne by shaking clothes. Marvin J. Bittner MD

Other rickettsioses Vector (often tick) Eschar, rickettsemia Vasculitis, serologic test Includes spotted fevers, rickettsialpox, typhus group

Typical Eschar at Tick Bite Site

Rickettsiae & spirochetes Rocky Mountain Spotted Fever Rickettsial biology Other rickettsioses Spirochetes

Vincent’s infection/Trench mouth Necrotizing ulcerative gingivitis Spirochetes/Rickettsia 8/23/07 Vincent’s infection/Trench mouth Necrotizing ulcerative gingivitis Synergistic gum infection Occurs in poor oral hygiene, malnutrition, immunocompromise Penicillin, oral hygiene . . . known as Vincent’s infection , trench mouth, or necrotizing ulcerative gingivitis. It is a synergistic gum infection in which the normal spirochetal oral flora participate. It occurs only when predisposing factors are present. The poor oral hygiene common in the trenches of World War I led to the recognition of this illness as trench mouth. It also occurs with malnutrion and with immunocompromised states, including leukemia. Treatment is penicillin and good oral hygiene. Marvin J. Bittner MD

Relapsing Fever Epidemic Endemic B. recurrentis Lice Human-lice E. Africa, Andes Borrelia spp Ornithodoros tick Human intruder Worldwide: High, warm, humid

Relapsing fever pathogenesis Spirochetemia Sequestration Antigenic modification Widespread (liver, spleen, CNS, heart, GI, kidney)

Relapsing fever presentation Abrupt fever, malaise, headache Arthralgia, cough, photophobia Conjunctival suffusion Petechiae Abdominal tenderness

Relapsing fever Recovery in 3-6 days Relapse in 7-10 days Untreated, 40% die Blood smear positive 70% Tetracycline, chloramphenicol

Spirochetes/Rickettsia 8/23/07 Lyme disease, United States In recent years the number of cases of Lyme disease in the U.S. has been growing. It has been over 15,000 cases a y ear. Marvin J. Bittner MD

Lyme disease cases by month, US, 1999 Spirochetes/Rickettsia 8/23/07 Lyme disease cases by month, US, 1999 Just as you would expect from a tickborne disease, cases are more common in the warmer months. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 A distinctive rash occurs in Lyme disease. It is called erythema chronicum migrans. It starts with a small red area. It expands into a large red circle There may be central clearing. Erythema chronicum migrans develops days to weeks after a tick bite. Ann Intern Med 1983;99:77. Erythema chronicum migrans. Rash of Lyme disease. Marvin J. Bittner MD

Erythema chronicum migrans Spirochetes/Rickettsia 8/23/07 Erythema chronicum migrans Marvin J. Bittner MD

Lyme diagnosis and treatment Spirochetes/Rickettsia 8/23/07 Lyme diagnosis and treatment Clinical, with special serology Treatment depends on stage Doxycycline, amoxicillin, cefuroxime IV penicillin or ceftriaxone (later) The diagnosis depends on the clinical picture. Very special serologic tests are needed because of cross-reactive antibodies. Treatment depends on the stage of disease. Early a variety of oral antibiotics have been effective. They include doxycycline, amoxicillin, and cefuroxime. In later disease intravenous penicillin or ceftriaxone have been used. Marvin J. Bittner MD

Spirochetes/Rickettsia 8/23/07 Tick repellent DEET Skin, clothing CNS toxicity (directions) Permethrin: Clothing Prevention measures may include tick repellent. DEET-containing insect repellents were effective applied to the skin or clothing. In some patients local bullous lesions or contact urticaria developed. About 10-15% of each dose can be recovered from the urine. High doses have been associated with serious reactions, including anaphylaxis, encephalopathy, and seizures, especially in children. Permethrin was studied as a pressurized spray for use on clothing and is advised for use with DEET. Some people are afraid of adverse effects on permethrin and DEET. So I did a Medline search. I found nothing new in the medical literature. Nonchemical approaches to prevention include wearing long clothing, avoiding outdoor activities entirely, and frequent inspections for ticks, especially of children. What if a patient gets bitten by a tick? Would prophylactic doxycycline stave off Lyme disease? Marvin J. Bittner MD

Key points: Lyme disease Spirochetes/Rickettsia 8/23/07 Key points: Lyme disease Tickborne B. burgdorferi Local: Erythema migrans Dissem: Heart, nerve, joint Persist: Fatigue, joint Doxycycline, ceftriaxone In summary, the puzzling distribution of Lyme disease--with many of the hundreds of cases seen each year concentrated in the coastal Northeast and in the upper Midwest--is now recognized a a consequence of its etiology: the spirochete Borrelia burgdorferi transmitted by ticks. Although the clinical picture of Lyme disease is varied and full of overlap, much of it can be viewed in terms of three stages: One, localized disease with an annular rash of erythema chronicum migrans at the tick bite site Two, disseminated disease with prominent manifestations involving the heart, nervous system, and joints Three, persistent disease with joint involvement and fatigue prominent Treatment is not settled. However, doxycycline and ceftriaxone are commonly used. Two frontiers of prevention are developing: Marvin J. Bittner MD

Frontiers of prevention Spirochetes/Rickettsia 8/23/07 Frontiers of prevention Vaccine: Withdrawn Tick avoidance An approach to tick avoidance was suggested by the author of a letter published in JAMA in January 1993. He wrote: “Following a case of erythema migrans at a Connecticut nudist camp, a request was made to the University of Connecticut Health Center for a physician who was willing to come to the camp and discuss Lyme disease. Not one to miss such an opportunity, I picked a Saturday in August to visit. . . . The nudist camp had abundant deer, woods, rocks, and grass—an ideal environment for the deer tick. . . . What was surprising was that deer tick bites were very unusual occurrences at the camp.” The author considered a number of explanations, concluding his letter by writing: Marvin J. Bittner MD

Many spirochetes tickborne Spirochetes/Rickettsia 8/23/07 Many spirochetes tickborne Not tickborne Syphilis: Sex Leptospirosis: Animal urine; early conjunctival suffusion, later liver & kidneys Tickborne: Borrelia relapsing fever, change antigens & relapse Many spirochetal diseases are tickborne. But, let’s not forget that a few spirochetal diseases are not tickborne. Syphilis is sexually transmissible. Leptospirosis is acquired from contact with animal urine and is remarkable for early conjunctival suffusion and later involvement of the liver and kidneys in severe cases. Returning to the tick diseases, we see some spirochetal diseases of the genus Borrelia. Relapsing fever has its relapses because of recurrent changes in borrelial antigens that allow the bacteria to slip past the immune system. Marvin J. Bittner MD

Spirochetal disease parallels Spirochetes/Rickettsia 8/23/07 Spirochetal disease parallels Lyme (& Syphilis) Initial rash: Erythema chron. mig. 2º stage: Nerves, heart, joints Late stage: Arthritis, fatigue Treatment: Penicillin, tetracycline If you think about Lyme disease, it has some parallels with another spirochetal disease, syphilis. Both have an initial rash. In the case of Lyme disease, it is erythema chronicum migrans. Both have a secondary stage. In the case of Lyme disease, it involves the nerves, cardiac conduciton, and joints. Both have a late, or tertiary stage. In the case of Lyme disease, it involves arthritis and fatigue. Both syphilis and Lyme disease can be treated with penicillin or tetracycline. Marvin J. Bittner MD

Rickettsia and spirochetes Spirochetes/Rickettsia 8/23/07 Rickettsia and spirochetes Rocky Mountain Spotted Fever Headache, rash, fever Tickborne No growth on routine culture Doxycycline The disease that I want you to study the most is Rocky Mountain Spotted Fever. When you see a patient with headache, rash, and fever, think Rocky Mountain Spotted Fever. But the rash may take a while to develop. This is a tickborne illness. So . . . if you see a patient with possible tick exposure and fever, think about Rocky Mountain Spotted Fever. You need to think about it because it won’t grow on routine cultures that you might do. You need to start doxycycline treatment, even in children, right away. Rocky Mountain Spotted Fever is caused by Ricketetsias rickettsii. Marvin J. Bittner MD

Rickettsia and spirochetes Spirochetes/Rickettsia 8/23/07 Rickettsia and spirochetes Other rickettsia Poor extracellular survival Suspect clinically Typhus: humans, lice Like other rickettsia, Rickettsia rickettsii has very poor survival out side of host cells. Like other rickettsia, it requires clinical suspicion in order todiagnose. Rocky Mountain Spotted Fever is the prototype of the spotted fever group. The prototype of the typhus group is epidemic typhus. Epidemic typhus is transmitted between humans, lice, and flying squirrels. Several genera of organisms are related to the rickettsiae, but now recognized in distinct genera. Marvin J. Bittner MD

Spirochetes Sequestration, antigenic change in relapsing fever Erythema chronicum migrans, tick in Lyme