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Exotic Infections

Ed Uthman, MD

Diplomate, American Board of Pathology

Revised 10 Nov 1998


The study of infectious diseases represents such a huge, multidisciplinary area of medicine that it is a recognized medical subspecialty requiring fellowship training after the completion of a residency in internal medicine or pediatrics. Even certified infectious disease subspecialists often further limit their practices to more restricted areas of infectious disease, such as"tropical medicine" and management of AIDS patients. For medical students, any treatment of infectious diseases at the survey level will of necessity leave out a huge amount of medical knowledge, so please consider this an apology in advance for when your Medicine attending drills you about "Lobo's disease," and you have no idea what it is.

Well, at least now you know how to spell it.

For this section, I have tried to select topics based on one or more of the following criteria. 1) The disease affects multiple organ systems and does not easily lend itself to coverage in an organ-specific curriculum. 2) The disease is of particular interest to anatomic pathologists because of striking morphologic findings. 3) The disease appeals to the imagination or sense of the dramatic.

Spirochetal Infections

Of course, syphilis is the biggie here, but it is covered exhaustively elsewhere.

Nonvenereal treponematoses

These include yaws, pinta, and bejel, all of which are caused by organisms of the genus Treponema, which are distinguishable from each other only by the clinical manifestations of the diseases they cause. In each of these diseases, the infection is transmitted primarily by direct contact between children living in squalid environments. It is possible that infection by these bugs confers some degree of protection against syphilis, but this has not been exploited by latter-day Edward Jenner wannabes. All of these organisms are easily wiped out by penicillin, and the world incidence of each has dropped dramatically.


Yaws (the origin of the word, first printed in English in 1679, is unknown), caused by Treponema pallidum ssp pertenue, occurs in warm, humid tropics. The primary lesion is a papillomatous skin lesion that heals spontaneously, only to be followed by the secondary lesions, which are large papillomatous nodules that are widely distributed over the skin surface. The late stage of the disease is characterized by gummas of various bones and the nasopharynx. The skin over the gummas may ulcerate.


Pinta (from the Spanish, "blemish"), which has become very rare, is limited to the warm arid tropical Americas (in particular, Mexico, Central America, and Colombia). It is caused by Treponema carateum. The primary lesions, which may persist for several years, are coalescing pruritic papules on the extremities, face, neck, chest, or abdomen. The secondary lesions are disseminated small, scaly papules, called pintids. These may become dyschromic (i.e., change from the normal color of the skin). Late lesions are achromic (without pigment).


Bejel (the Arabic word for the disease) is known by many names in local languages as a form of syphilis which is not sexually transmitted and occurs in children. Probably the most illuminating appellation to remember this disease by is endemic syphilis. The causative organism is dubbed Treponema pallidum ssp endemicum. Transmission can be by direct contact, and also (in contradistinction to all the other treponemal diseases) via fomites, as in sharing drinking vessels and eating utensils. Except for the fact that the primary lesion (which is probably in the oral mucosa) is rarely observed, the disease is virtually identical to syphilis, with gummas, condylomata lata, periostitis, the whole nine yards.

Lyme disease

Lyme disease, a multisystem infection caused by Borrelia burgdorferi (a non-treponemal spirochete), is interesting from both medical and sociological standpoints. One of the several diseases about which swirls a maelstrom of scientific, political, and sociological controversy, Lyme disease was only recently recognized (1975) as a tick-borne infection carried by several species of"deer ticks" of the genus Ixodes. Experimentally it has been shown that a tick must be attached to a mammalian host (rodent) for at least 24 hours before host infection occurs, but whether this is true in humans is unknown, and there are not an awful lot of volunteers chomping at the bit to find out.

Lyme disease occurs in stages, like most of the other spirochetal diseases.

While the treatment of Lyme disease in its early stages is simple, treatment for frank neurologic disease involves intravenous ceftriaxone for a whole month, which is both expensive and disabling. Clearly, it is best to make the diagnosis at the erythema migrans stage, when diagnostic clinical features are manifest and when treatment is quick and inexpensive. My advice is to keep your feelers out in the derm clinic to see as many cases of ECM that come along. This is one diagnosis you don't want to miss when you get out on your own.

One of the best ways to appreciate the difficulties involved in diagnosing and managing Lyme disease is to read about it in a patient's own words.


The rickettsiae are all Gram-negative coccobacilli which are obligate intracellular parasites. With the exception of Coxiella burnetii (the causative agent of Q fever), none can survive outside a host for very long. With the exception of Rickettsia prowazekii (louse-borne typhus) humans are incidental hosts, i.e., not necessary to propagate the organism in nature. The rickettsiae are so infectious (even a single C. burnetii organism is capable of producing disease in a human) that they are extremely dangerous to handle in a lab.

Ricketts was the pathologist who first detected the organisms that cause Rocky Mountain spotted fever and louse-borne typhus. Unfortunately, he also became infected by the latter and died in 1910 in Mexico City at age 39. Everyone felt so bad about Ricketts that they not only named the genus and species of the former organism (Rickettsia rickettsii) after him, but also the whole taxonomic Family (Rickettsiaceae) and even the Order (Rickettsiales). I imagine that some of the more emotionally volatile members of the microbiology community wanted to change the whole Kingdom name from "Protista" to "Rickettsista," but cooler heads prevailed.

Most of us subsistence-level laboratorians take to heart the lesson of Howard T. Ricketts (see sidebar) and do not even try to isolate these organisms in clinical labs, referring such requests to Andromeda Strain-type facilities elsewhere, preferably far away. Detection of antibodies to rickettsiae is commonly available, but since antibodies show up over a week after the patient gets deathly sick, once again you are on your own to use clinical judgement as to when to begin therapy. Perhaps polymerase chain reaction will eventually save the day for the physician who is judgementally challenged.

Rocky Mountain spotted fever

Rocky Mountain spotted fever is one of several "spotted fevers" (those characterized by "spots" on the skin) that occur worldwide. RMSF, caused by R. rickettsii, is the only one of importance in the U.S. Despite the name, the disease is much more common in the Southeast states than in the Rocky Mountains. The disease is vectored by the Dermacentor tick. The pathogens are not released into the human host (from the tick salivary gland) until after 6 to 10 hours of feeding by the tick. After an average incubation time of a week, the clinical disease begins with fever, myalgia, and headache. The diagnostic rash does not appear until 3 to 5 days after the onset of systemic symptoms. It begins as a maculopapular rash around the wrist and ankles and characteristically involves the palms and soles (there are not too many other rashes that do this, so this is a helpful distinguishing characteristic). The individual lesions may have central petechial hemorrhages, which reflect destruction of small blood vessels by the pathogens, which infect vascular endothelial cells in large numbers. Interestingly, the histologic findings in the affected skin are rather nonspecific, such that routine microscopic examination of a skin biopsy is generally not useful in diagnosis. On the other hand, skin biopsy may be useful for studies aimed at detecting the organisms by direct immunofluorescence. Treatment of RMSF is a no-brainer, involving oral tetracycline or other cheapo oral antimicrobial. The problem in RMSF is making a timely diagnosis, so that the disease process does not "get ahead of you." Therefore, experienced clinicians maintain a high index of suspicion for this disease when confronted with a previously healthy febrile patient.


Rickettsialpox, caused by R. akari, is transmitted among mice via mouse mites. Humans are incidental hosts. An outbreak in New York as recently as 1981 suggests the need for vigilance in the control of rodent pests.

An eschar (pronounced ESS-car) is a dried scab-like crust on the skin or mucous membrane. Eschars are most typically associated with burns, but they can result from necrotizing inflammatory lesions (like rickettsialpox and anthrax) as well.

The primary lesion at the site of the mite bite is a papule that degenerates into an eschar. Within a week, the patient develops chills, fever, and headache, followed by a papulovesicular rash that may be confused with chickenpox. Although rickettsialpox is only rarely fatal and typically resolves spontaneously, it does do better with antimicrobial treatment, so it is important to recognize it for what it is, rather than writing it off as an atypical case of chickenpox.

Q fever

Q fever is the odd man out among the rickettsioses. First, the causative organism, Coxiella burnetii, is capable of surviving outside a host for long periods of time, so that it may be transmitted by aerosol (like a viral rhinitis).

The "Q" is short for "query," coined by E. H. Derrick, who first described the disease in 1935. I think Derrick deserves praise for having the intellectual honesty to admit his ignorance. I cannot see someone today describing an "I-don't-know-what-it-is tumor," a "sure-got-me-stumped syndrome," or a "don't-ask-me-I-just-work-here fever."

Second, the organism, unlike the other rickettsiae, enters the host cell passively and resides in a phagolysosome (which is more like a chlamydia than a rickettsia, which typically lives free in the cytoplasm). Finally, to the disappointment of all those Rocky Mountain spotted fever fans out there, Q fever does not produce a rash.

C. burnetii is maintained in nature by transmission among ticks. Mammalian hosts are infected incidentally, but none but humans get sick. Humans are typically infected by occupational contact with aerosols generated from the blood and tissues (including placentas) of infected mammals. Farmers, veterinarians, and abattoir workers are most at risk. The organisms multiply in the lungs and are then distributed throughout the body via the bloodstream. Infections become established in various sites to produce the clinical manifestations of Q fever, which include pneumonia, endocarditis, hepatitis, osteomyelitis, and encephalitis. The disease is rarely fatal. A presumptive diagnosis is made by correlation of the occupational history with the clinical findings, but definitive diagnosis generally must await serologic confirmation.


Typhus, from the Greek word for "stupor," occurs in several forms but the one we will discuss here is epidemic or louse-borne typhus, caused by Rickettsia prowazekii, and vectored through the human body louse, Pediculus humanus corporis.

Notice that even though Ricketts died of an infection by this organism, the species was not named after him. Rest assured, however, that the species namesake, Austrian microbiologist Stanislaus Joseph von Prowazek, did in fact die of typhus, too. Parenthetically, the species was named for Prowazek by H. da Roche Lima, who himself was eponymized into the genus name Rochalimaea, which has now been axed and grouped into the genus Bartonella, named after Barton, who discovered Bartonella bacilliformis. Barton did not die from bartonellosis. That was left to Daniel Carrión, who died of Bartonella infection while investigating cases of same in his native Peru.

The organism lives in the insect's gut and is passed in its feces, which it drops right after a blood meal. The host scratches the bite and unwittingly rubs the inoculum into the wound. If it's any consolation for the human victim, the rickettsia also kills the flea by obstructing it's tiny little intestine.

From the wound site, the proliferating organism spreads hematogenously and infects vascular endothelial cells, causing vasculitis and/or perivasculitis, similar to the situation with RMSF. The first clinical problems relate to septicemia, in that the patient develops a progressive and unremitting fever and is eventually lain prostrate by the disease. On about the fifth day of illness, the characteristic rash develops, beginning in the axillary folds and upper trunk and spreads centrifugally (Cf., RMSF, where the rash spreads centripetally from the extremities). The disease usually resolves on its own, but some patients go on to develop complications (including pneumonia, neurological dysfunctions, and renal failure) and die.

In 1528, a French army besieging Naples, garrisoned by an army of Holy Roman Emperor Charles V, was wiped out (19,000 killed of 25,000 total) by typhus. Had this not happened, Europe would have been left with a much stronger Pope Clement VII, and a much stronger France under Francis I, at a time when Protestantism was just a tender young seedling. It's hard to imagine how European/American history would have turned out had Lutheranism been smothered in it's cradle. Suffice it to say that it is likely you would be reading this in French instead of English.

The mortality rate is highly variable, but the elderly are worst affected, while children tend to sustain the infection with minimal clinical manifestations. There is an especially mild form of R. prowazekii infection, called Brill-Zinsser disease, which apparently represents a recrudescence of a previous case of typhus, presumably due to stress or an impaired immune system.

As you might expect about any disease that is spread only by louse infestation, typhus is associated with conditions of utter deprivation and hardship, such as during long military campaigns. The disease has great historical importance, but it is currently extremely rare in the U.S. (no cases reported in 1994, compared with 441 cases of RMSF).


Ehrlichiosis is mentioned because it is the newest rickettsiosis, the first U.S. case being described in 1986 (although animal infections were described as early as 1935). The genus Ehrlichia lives inside cytoplasmic vacuoles of the host cells, like Coxiella and Chlamydia, but it is actually more closely related to other rickettsia than to those two. There are two forms of ehrlichiosis. The more common one is human monocytic ehrlichiosis (HME), caused by Ehrlichia chaffeensis, which is maintained in nature by propagation through the Lone Star tick (Amblyomma americanum). The other form is human granluocytic ehrlichiosis (HGE), caused by an organism "closely related" to Ehrlichia equi. This pathogen is vectored by deer (Ixodes scapularis) and dog (Dermacentor variabilis) ticks. In either case patients give a history of tick exposure within a month prior to presentation.

After entering the body at the site of the tick bite, the pathogens proceed to the target cells in the bone marrow and lymphoreticular system. The organisms form clusters, called morulae, which show up at the light microscopic level as intracytoplasmic inclusions, predominantly in monocytes and macrophages (HME) and neutrophils (HGE). The disease is clinically manifest as fever, rash, leukopenia, thrombocytopenia, and hepatitis. There are numerous clinical similarities between ehrlichiosis and Rocky Mountain spotted fever, which may lead to misdiagnosis of one or the other. Thankfully, both respond to treatment with tetracycline.

Other Eubacterial Infections


Plague is rare in the U.S., but it still does occur here (14 cases nationwide in 1994), as it does in a few other countries of the world. The primary interest is historical, however, and the very name of the disease is the same as the generic term for any pandemic infection that lays waste to the human landscape.

Although the squalid conditions in which the plague thrives have existed through much of history, only three well-documented (and one "maybe") pandemics have occurred:

This is the "maybe." Around 1050 B.C., according to the Bible [1 Samuel 5], the Philistines defeated the Israelites at the Battle of Ebenezer and, not having seen Raiders of the Lost Ark, unwisely carried off the Ark of the Covenant. This did not go unnoticed by Yahweh, who smote the offenders with a disease that apparently involved "tumors" (buboes?) and rats. Although He tailored Yersinia pestis to specifically punish the Philistines, Yahweh apparently delegated the leg work to Mother Nature, who, being somewhat less politically inclined, saw to it that the epidemic spread indiscriminately throughout Israel, killing some 50,000 people, irrespective of persuasion.

The Plague of Justinian was possibly the most devastating pestilence of the ancient world. Lasting fifty years, it arrived in the Imperial capital, Constantinople, in 542 A.D. Mortality in the city reached as high as 10,000 per day. Ships were loaded with the dead, towed out to sea, and abandoned. Fortification towers were unroofed, filled with corpses, then re-roofed.

Well, the Romans were always admired for their civil engineering.

The most famous pandemic was the Black Death, which, like a lot of the perturbations that perennially rattled the cage of Western Civilization (Aryans, Mongols, Huns, Turks, gunpowder, etc) originated in Asia. From 1346 to 1361, the epidemic killed up to one-third of the population of Europe. One of the many effects was the abandonment of Greenland by the Norwegians. Since the North American colony of Vinland was probably supplied by the Greenlanders, and had to be subsequently abandoned, one could speculate that the Black Death may have kept the Americas from undergoing widespread colonization by the Scandinavians. This would have given them a huge head start on the Spanish, Portuguese, French, and English. Had the Black Death never occurred, you might be reading this in Norwegian instead of English.

The last pandemic ravaged Europe in the seventeenth century and is best known to us as the Plague of London, 1665-66. This is the one chronicled by Samuel Pepys in his diary (which most of us didn't mind reading in high school because of all the sexual content). Since the printing press was now available, this was the first epidemic in which the populace was kept thoroughly informed of the latest in cutting-edge medical knowledge. One pamphlet informed its readers that the plague was caused by "eating radishes, a cat catter wouling, immoderate eating of caviare and anchovies, tame pigeons that flew up and down an alley, and drinking strong heady beer." Rumors that syphilis prevented the disease caused the gentlemen of London to storm local houses of ill-repute. English physicians apparently knew better; many just left the country.

The specific plague referred to here is that infection caused by the Gram-negative rod Yersinia pestis, a member of the family Enterobacteriaceae, which includes many of our old friends (Escherichia, Klebsiella, Enterobacter, Salmonella, Shigella, etc).

Plague is a zoonosis that is propagated through mammals and vectored predominantly by the oriental rat flea, Xenopsylla cheopis. Like with most bacterial zoonoses, humans are incidental hosts and are not critical to propagation of the microorganism in nature. The classical animal reservoirs are the urban rat (Rattus rattus) and domesticated rat (Rattus norvegicus). These are responsible for urban plague outbreaks. Currently, native cases in the U.S. occur in rural areas of the Southwest, where the so-called sylvatic plague is reservoired in the ground squirrel, rock squirrel, and prairie dog. Human victims are typically Native Americans living on reservations. In the insect vector, the bacillus multiplies in the gut, where it produces coagulase, an enzyme which coagulates blood. When the flea feeds on mammalian blood, the coagulase causes the blood to clot and obstruct the flea's GI tract. This causes the flea to regurgitate large numbers of organisms into the wound, from which they spread to regional lymph nodes and are phagocytosed. The bugs are happy to proliferate inside the phagocytes, from which they emerge and spread hematogenously. There are three main forms of the disease:

The clinical diagnosis of plague is fairly straightforward for the physician who has a high index of suspicion. Confirmation is by serology or culture of the aspirate of a bubo. These tests are generally sloughed on a CDC lab, but a local lab can help you by doing a Gram stain on the aspirate. The bipolar Gram-negative rods are present in very large numbers.


Cholera is another one of those epic blights on the human condition, but the Bible, which is usually quite attuned to such things, does not mention it. Cholera did not enter the European realm of experience until 1817. Another import from Asia, cholera did much damage to the populations of Europe and the U.S. in the nineteenth and early twentieth centuries, but currently the disease is regularly present only in southern Asia. Thirty-nine U.S. cases were reported in 1994, but they all were imported.

According to the Old Testament, Yahweh did include bowel disease in His punitive armamentarium, but the only case mentioned is too chronic and painful to be cholera: "And after all this, Yahweh struck [King Jehoram of Judah] down with an incurable disease of the bowels; ...and when two years were over and his last hour had come, his bowels dropped out with disease, and he died in great pain." [2 Chronicles 18-19] This sounds to me like a chronic inflammatory bowel disease with eventual rectal prolapse. Diagnostic possibilities include chronic ulcerative colitis, solitary rectal ulcer syndrome, and infestation by whipworms (Trichuris trichiura).

In 1853, London anesthesiologist John Snow actually figured out that cholera was caused by an agent in drinking water contaminated by sewage. This is quite extraordinary, since Pasteur was not to elucidate the germ theory of disease until 1861, and Koch was not to discover the cholera bacillus until 1883. Snow traced a cluster of 700 cholera deaths to an area surrounding the Broad Street water pump in Soho. He approached the Board of Guardians of the area and suggested that the pump handle be removed. Although skeptical, the Board was also desperate, so they complied. The epidemic ended three days later. However, the Board (which must have been the direct ancestor of the San Antonio City Council) blew off Snow's theory and attributed the disease to "some atmospheric or other widely diffused agent still to be discovered." I wonder if they have fluoridated water in Soho yet.

"Cholera" is a classical Greek medical term, but what the Greeks called "cholera" was not apparently what we use the term for. The Greek cholera seemed to signify more of an indigestion-type illness with bloating, vomiting, and abdominal pain, or "biliousness." The Greeks thought this was due to an excess in bile, which is understandable, since many of the victims vomited up green material. Unfortunately, while the Greeks were great at math, they were way off base in terms of disease pathogenesis. Fortunately, the collective human genome mutated sometime in the fifteenth century, resulting in a brain that could figure out biology but (with the exception of a few throwbacks) had lost the ability to do math.

Cholera is caused by Vibrio cholerae, a short, curved Gram-negative rod, which is closely related to, but not actually a member of the family Enterobacteriaceae. The bug does its dirty deeds by way of secreting an exotoxin (specifically an enterotoxin) that increases the activity of adenylate cyclase in small bowel epithelial cells. This causes the cells to actively secrete electrolytes into the intestinal lumen. Whither goeth electrolytes, so goeth water, so severe watery diarrhea is the clinical result. In an excellent example of gene cooperation, the bug also secretes a neuraminidase which degrades gangliosides on the host cell membrane to produce a monosialyl product, which acts as the specific receptor for the enterotoxin. There are two main strains of V. cholerae, the classic strain, and the El Tor biotype. During the first three-quarters of the twentieth century, the El Tor biotype, which in general is kinder and gentler than the classic strain, gradually replaced the latter among human epidemics. However, the classic strain came back with a vengeance in 1982, and now, as of 1992, there has arisen a mutated variant of the El Tor biotype to which no population immunity exists. Natural selection marches on.

As you might expect, cholera has the potential of developing in situations where there is insufficient separation between drinking water and sewage. This can be a chronic state in miserably impoverished areas, but cholera epidemics are always feared in any part of the world in the aftermath of disasters in which the public health infrastructure breaks down (e.g., the recent earthquake in Kobe, Japan).

The pathogenesis of cholera is quite simple, in that all findings result from the great amounts of fluids and electrolytes lost through the watery diarrhea. The disease at its worst can kill within two to three hours of the first symptoms. Hypotension, due to loss of intravascular volume, may occur within one hour. The stool is not odorous, and its appearance has been likened to that of "rice water" (a metaphor not unexpected in a native Asian disease; Americans would probably describe the same bedpan contents as "public school cafeteria vegetable soup broth stools"). Vomiting often occurs in the early stages of the disease, which makes oral replacement of fluids a problem. The mental state of the cholera patient has been described as "detached." Death occurs from hypovolemic shock.

The stools contain large numbers of V. cholerae, which can be presumptively identified by observing their "shooting star" motility on direct darkfield exam, and conclusively identified by culture. In real-world situation, however, diagnosis is made by the history and physical exam, and lab techniques are reserved for epidemiological investigation.

Other vibrios

Other vibrios are mentioned mainly to distinguish them from V. cholerae. The other species which causes a diarrheal illness is Vibrio parahaemolyticus which also produces an enterotoxin (albeit a less potent one than its cholera cousin) but also is capable of causing an acute colitis by invading large bowel mucosa (which cholera does not do). As a halophilic (salt-loving) Vibrio, V. parahaemolyticus, thrives well in seawater. Outbreaks of diarrhea follow ingestion of poorly-cooked shrimp or crabmeat, which may give you second thoughts about magnanimously having the whole class over for a good ol' fashioned Louisiana shrimp boil to celebrate the end of the pathology course. Also worthy of note are V. vulnificus and V. alginolyticus, both of which are also halophilic. These, however, are not typically associated with diarrhea, but with wound infections and septicemia. V. vulnificus is especially prone to cause serious systemic infections in cirrhotic patients; the mortality of such infections is 50%.

Note: Please send all constructive comments regarding this monograph to Ed Uthman, MD .

This article is provided "as is" without any express or implied warranties. While reasonable effort has been taken to ensure the accuracy of the information, the author assumes no responsibility for errors or omissions, or for damages resulting from use of the information herein.

Copyright (c) 1994-98, Edward O. Uthman. This material may be reformatted and/or freely distributed via online services or other media, as long as it is not substantively altered. Authors, educators, and others are welcome to use any ideas presented herein, but I would ask for acknowledgment in any published work derived therefrom.

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