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RICKETTSIOSES: CURRENT PROBLEMS OF CLINICAL INTEREST

THEODORE E. WOODWARD
Department of Medicine, University of Maryland School of Medicine and Hospital Baltimore, Maryland 21201, U.S.A.

At least one rickettsial disease is present in most countries whenever attempts have been made to identify them. Rats, fleas and crowded populations, particularly in port cities, favor the presence of murine typhus fever. Its close relative, epidemic louse-borne typhus fever, has ravaged humans during wars, famine or in poverty and now exists in the cold environments of Europe, Africa, the Middle East, the Asian subcontinent, Latin and South America. Louseborne typhus fever remains an important cause of morbidity and mortality where environmental and socio-economic conditions allow proper interplay between the microbe, susceptible populations and the vector. During 1976, a total of 8,065 cases with 106 deaths were reported to WHO with principal foci in the highlands of Central Africa including Burundi, Rwanda and Southern Uganda. A few cases were reported from Nigeria and only two from Algeria. Bolivia, Ecuador and Peru in South America reported a total of 223 cases with eight deaths. Ethiopia has reported no cases since 1971. (Weekly Epidemiological Record, World Health Organization, Geneva, 8 July 1977, pp. 221-223). Patients with Brill-Zinsser disease are the reappearing ghosts of typhus fever and serve as human reservoirs of Rickettsia prowazeki.

Rocky Mountain spotted fever in the United States and Sao Paulo typhus in Brazil are the most significant and clinically severe types of the tick-borne group. There has been a steady increase in the number of patients with Rocky Mountain spotted fever in the United States. For many years, approximately 500 cases occurred annually with a mortality of about 20 percent prior to the availability of antibiotics. After introduction of specific therapy in 1948, the number of reported cases decreased to a low of about 200 in 1959, 1960, and 1961. The decrease was probably influenced by the widespread use of broad spectrum antibiotics early in the illness and under-reporting.

Since 1969, there has been a gradual increase in annual incidence with approximately 900 cases reported in 1975 and 1976, and a cumulative total of 1,102 for the forty-ninth week of 1977, ending December 11, (Morbidity and Mortality Weekly Report. Center for Disease Control, U.S. Department of Health, Education and Welfare, P.H.S. December 16, 1977, vol. 26, nº 50). Transformation of farms into housing developments and recreation in wooded areas probably accounts for the added exposure to infected ticks particularly in the South Atlantic States where the largest number of cases occur.

In the Eastern Hemisphere and elswhere, the tick-borne rickettsioses are milder and known variously as fièvre boutonneuse, South African, North Asian, Kenya, Indian, Siberian, Queensland tick-typhus and others. Mite-borne rickettsialpox with its rodent reservoir is meddlesome rather than important.

Scrub typhus fever (tsutsugamushi disease) occurs in Japan, China, Australia, the Southern Islands, Malaya, Indonesia, Burma, Thailand and the Asian subcontinent. It is mite-borne with a rodent reservoir and can be mild or lethal.

Q fever is the lone rickettsial infection unassociated with an exanthem which is mild unless manifested in the chronic forms of hepatitis or endocarditis which are become increasingly clinically significant.

Unlike smallpox, said to be on the verge of extermination, human rickettsial diseases will persist because rickettsiae and their animal-vector host have adapted to a firmly established existence with man as an accidental sporadic victim. Small mammals become inapparently ill and rickettsiae persist indefinitely in their tissues. Ticks, fleas and mites survive their infections and often transmit the agent transovarially. Only lice die of typhus infection. It remains unclear whether R. mooseri (murine typhus) may mutate to the characteristic R. prowazeki by passage through lice. In contrast to variola with its distinctive vesicle, patients with typhus and recurrent typhus often escape diagnosis which can make them a continuing source of infection. It is conceivable that patients with other rickettsial diseases, such as Rocky Mountain spotted fever, murine typhus and Q fever, may experience recurrent infections of the Brill-Zinsser pattern. This type of recrudescence has not been reported.

Physicians must learn to accept that sporadic cases of rickettsial diseases will occur and they must learn to identify and treat them, based on suspicion and good clinical judgement, aided by laboratory tests. Judicious use of vaccines and other control measures should help limit them to a sporadic existence.

An excellent review (1) and the comprehensive statistical reports of the World Health Organization, describe well the global presence of rickettsial diseases which will not be recounted.

The orientation of this paper is clinical. Patients seriously ill with rickettsia] diseases recover promptly with proper supportive measures and specific effective antibiotics. Unfortunately, delays in making an early specific diagnosis often allow unabated vascular and tissue changes which lead to death or other sequelae.

To be described are: 1) the clinical findings of an early case and the pathophysiologic abnormalities and management of a patient severely ill with Rocky Mountain spotted fever which is the prototype of severe rickettsial infection and 2) a method of confirming the presence of rickettsiae in human skin as early as the third febrile day of Rocky Mountain spotted fever.

ROCKY MOUNTAIN SPOTTED FEVER

Illustrative Case Report of Severe Rocky Mountain Spotted Fever (2,3)

A previously healthy 4-1/2 year old boy was hospitalized in May because of fever and rash of about eight and five days, respectively. Despite symptomatic treatment and intramuscular penicillin given four days before admission, the child's condition deteriorated. The rash began as "little pink-red spots" on the forearm which the mother assumed to be measles.

The child lost considerable weight because of anorexia, mild diarrhea and vomiting which occasionally produced coffee-ground material. Generalized malaise, frontal headache, fever of 102º to 106º and rash persisted.

As the child's condition worsened, the eruption spread to the upper arms, legs face and trunk; it was most extensive on the arms and legs. Two days before hospitalization, the rash assumed the appearance of blood blisters.

Because of her son's increasing lethargy, the mother sought medical attention. In hospital, multiple laboratory tests showed: normal cerebro-spinal fluid with negative Gram stain; no evidence of pathogenic bacteria in fluid from a skin lesion; hemoglobin 12.8 gm.%; 10,500 white blood cells/cu mm with a marked left shift; serum sodium 115 mEq/liter. Before referral, the child was given 2 grams of ampicillin intravenously.

Examination on the eighth day of illness revealed a toxic, lethargic, semistuporous child responsive only to painful stimuli. A generalized petechial and confluent hemorrhagic eruption, which did not fade on pressure, was prominent on his trunk, arms and legs, with involvement of the palms and soles.

Findings included temperature 102.8 F, pulse 160, blood pressure 90/60, marked facial edema, photophobia moderate conjunctival injection and normal fundus. Tonsils were hypertrophied. Fresh and dried blood appeared on the teeth and gingivae. Nuchal rigidity was minimal, the liver moderately enlarged and spleen not palpable. Moderately severe peripheral edema and cyanosis of the left great toe, with poor capillary filling, were noted.

There was no history of measles or known recent exposure; his measles immunization status was unknown. At home, all siblings were well except for a 10 year old half-brother who was moderately ill with fever and rash.

When questioned specifically, the mother stated that four days before the onset of illness she had removed an engorged tick embedded behind the child's left ear.

Laboratory Values. Hemoglobin 12.0 gm.%, hematocrit 40%, white blood count 10,000/cu mm, pharyngeal smear and culture - no pathogens isolated, platelets 16,000, prothrombin time and partial thromboplastin time - prolonged, fibrinogenvery low; serum electrolytes: sodium 112 mEq/liter, chlorides 82 mEq/liter, carbon dioxide 19 mEq/liter, potassium 4.4 mEq/liter, blood urea nitrogen 35mg%, serum albulin 1.8 gm.%; initially, urine was not obtainable. Disseminated intravascular coagulopathy (DIC) was assumed to be present based on the hemorrhagic diathesis involving the skin and gums, the hemogram and serum clotting values.

Treatment. On hospitalization, the child was monitored in an intensive care unit, and within two hours was treated with chloramphenicol given intravenously. General supportive management included oxygen therapy, corticosteroids and judicious administration of dextrose and isotonic saline, given intravenously, sufficient to support the circulation, maintain urinary output and avoid induction of further tissue edema. Heparin was not given.

Course. The child's blood pressure remained stable during the first twentyfour hours. He remained semi-stuporous, agitated and critically ill. The rash became more confluent and hemorrhagic.

Within forty-eight hours of hospitalization, the clinical diagnosis of Rocky Mountain spotted fever was presumptively confirmed serologically by the finding of Proteus OX-2 agglutinins in the titer of 1:160. Cultures of the pharynx, blood and cerebrospinal fluid were negative. Penicillin was discontinued. Treatment with chloramphenicol, corticosteroids and fluids led to defervescence in thirty hours.

The child responded by the third hospital day (eleventh day of illness), when the electroencephalogram showed evidence of diffuse encephalopathy.

One week later, a second electroencephalogram showed improvement corresponding with the patient's good progress. After seventeen days of hospitalization, he was discharged afebrile, without rash, and with only a slight personality change. The convalescent serologic titers were: Proteus OX-2 1:640 and complement-fixation for Rocky Mountain spotted fever 1:128. The electroencephalogram was normal in one year when the child was clinically well.

Case Report of Rocky Mountain Spotted Fever During First Week.

During early May, 1976, a 4 year old girl who lived in a rural wooded area in Maryland developed fever with irritability, vomiting and headache. For four days the headache worsened, she felt chilly without actual chills and each day the temperature exceeded 103ºF in the afternoon with slightly lower morning levels. Increasing fever with prostration and myalgia prompted the mother to seek medical attention.

When examined on the fourth febrile day, the child was restless and complained of frontal headache; temperature 104.5º, pulse - 110, blood pressure 90/70, injected conjunctivae, normal lung findings, heart normal size, no murmurs, slight hepatomegaly, spleen palpable 2.0 cm. below costal margin, genitalia normal. Examination of extremities and CNS normal.

Rash: A distinct pink macular exanthem involved the palms, soles, forearms, legs, thighs and buttocks with a few individual lesions on the trunk. The macules were irregular in outline, measuring 3 to 6 mm. in diameter and faded on pressure.

These findings plus the history of removal of a tick from the scalp a week prior to onset strongly suggested Rocky Mountain spotted fever.

Laboratory findings were: Hemoglobin 14.0 gms., hematocrit 40, WBC 6,350 cu mm., differential normal, slight albuminuria, serum electrolytes, BUN, glucose normal. Two male guinea pigs were inoculated each with 4.0 ml of whole blood intraperitoneally, blood serum was saved for serologic tests and a full section of a macular skin lesion was excised for identification of rickettsia.

Based on clinical manifestations, chloramphenicol was given orally with an initial dose of 50 mg/kilo body weight and similar daily doses divided equally every six hours. A high calorie diet rich in protein was used.

Within thirty-six hours the headache and irritability abated, the-child appeared stronger and the temperature reached normal levels in 3.0 days. With defervescence, the rash, which did not progress, was faint and antibiotic treatment was stopped.

Initial serum specimens were negative for antibodies when tested by the Proteus OX-19 (Weil-Felix), complement fixation (C.F.) and rickettsial microagglutination tests (M.A.) Later specimens obtained on the twelfth and twentyfirst days of illness were positive as follows: W-F:160, 320; C.F.:32, 64; and M.A.: 16, 32, respectively. Guinea pigs developed febrile reactions and after severall transfers of blood to other animals, rickettsiae were identified in several tissues by smear; serologic tests were positive. Figure 1 shows fluorescent stained Rickettsia rickettsii in the skin lesion taken on the fourth day.

Recovery was complete.



Fig. 1 :

R. rickettsii in skin section of a pink macule taken on about the fourth day of R.M.S.F.

Preparation by Immune Fluorescense (I.F.) x 900.

Prompt Confirmation of Rocky Mountain Spotted Fever; Identification of Rickettsiae in Skin Tissues.

The physician may mistake the clues of headaches, fever, myalgia and rash of tick-borne spotted fever for measles, other viral illness or meningococcemia. These errors, which can lead to delay in treatment, are evidenced by mortality rates of about 7 percent in patients with Rocky Mountain spotted fever in the United States.

Available confirmatory laboratory aids for rickettsial diseases are the Weil-Felix (W-F), complement fixation (C.F.), rickettsial microagglutination (M.A.), and indirect fluorescent antibody (I.F.A.) reactions or the more tedious isolation of causative rickettsia in animals or tissue culture. Regardless of the serologic test chosen, results are available late in illness when serious or irreversible vascular changes or death may have occurred.

Recent attempts to provide earlier diagnostic help include identification of in either monocytes (4) or tissues (5) of experimentally infected animals. Rickettsiae were identified in stained culture monocytes of infected monkeys and by direct or indirect immunofluorescence of tissues of infected animals.

We have successfully identified R. rickettsii in skin specimens obtained by biopsy from patients with R.M.S.F. taken during the early and later stages of illness (6).

Five patients with characteristic manifestations of R.M.S.F. have been studied. A small section of skin from a fresh pink macule of a 4 year old girl was taken between the third and fourth days of illness. The specimen was placed in saline, transported on ice and processed promptly. Utilizing the indirect immune fluorescence (I.F.) technique, rickettsiae were identified within about four hours laboratory work time. The procedure was performed by reacting high titered antiserum conjugated with fluorescent isothiocyanate which was placed on properly sectioned skin specimens and examined by dark field microscopy. Rickettsiae have an identifiable morphology and characteristic staining property.

Shown in figure 1 is the I.F. preparation of the rickettsia visualized in the patient, who was shown to have R.M.S.F. by all other laboratory tests.

Rickettsiae were also visualized in other patients whose macular skin lesions were examined later in the first week of illness and in a severely ill, comatose girl on about the eighth day of R.M.S.F. Rickettsiae similar to those shown in figure 1 were visualized although fewer organisms were present.

A more simplified technique of using a punch skin biopsy or needle aspiration of a macule or purpuric lesion should be adaptable to other rickettsial diseases

and certain infections associated with a rash. A recent report has described paraffin fixation of tissue, such as kidney, and identification of rickettsia by I.F.(7) . This technique should be useful for retrospective study of preserved tissues.

There is a significant lag-time between the clinical suspicion of R.M.S.F. and other rickettsia] diseases (when treatment should be instituted) and laboratory confirmation. Specific antibiotic treatment given when the exanthem appears, or not later than about the sixth day of illness, is usually followed by prompt and full recovery.

When therapy is delayed until the second week of illness, extensive vascular and tissue changes may have occurred which makes recovery more difficult, delayed and occasionally followed by death. Management for these patients must include prompt specific chemotherapy and enlightened supportive care which have been described elsewhere. Recovery may occur even at the late stage, although it may be delayed and associated with residuae.

Physicians are not acquainted with rickettsial diseases because of their sporadic occurrence and during the early stages of illness, the presence of fever, headache, malaise and myalgia is non-specific. Many infectious diseases are similar in manifestations at this stage and with the appearance of a rash such infections as measles, meningococcemia and others become suspect. A method of confirmation of one of the serious rickettsioses (R.M.S.F.) by I.F. identification of rickettsiae in early and late skin lesions is now available. In selected patients, this confirmatory test is positive before the results of standard serologic procedures are available.

Certain unsolved problems in pathophysiology and clinical management awaiting solution are (2) :

Unsolved Problems

Pathophysiologic: It is unknown whether the increase in capillary permeability and tissue hemorrhages results from direct effect of rickettsiae in the vascular endothelium, by the toxin, by a combination of each or an immunopathologic reaction. Serial studies of skin lesions utilizing I.F. and other techniques would help clarify this puzzle and help determine whether corticosteroids abate this abnormality.

Increase in capillary permeability with leakage of fluid, electrolytes and albumin accounts for the mild hypovolemia and increase in extra-cellular space. It is unknown whether there is intracellular expansion. Isotopic techniques might help settle this point.

Many features of disseminated intravascular coagulopathy are present in severely ill patients although the mechanism is unclear. Heparin does not appear to be needed therapeutically. Studies of the coagulation and complement systems in primates infected with R. rickettsii intravenously showed that hyperfibrinogenemia, thrombocytopenia, prolonged prothrombin and activated partial thromboplastin times with increased serum fibrin/fibrinogen degradation products occurred with the onset of fever and rickettsiemia. Reactions were greater in fatally ill monkeys. Decreases in amounts of complement fractions C2, C3 occurred in monkeys which developed peripheral gangrenous ecchymoses. Apparently, the hemostatic disturbances in fulminant infection is a direct effect of the infectious vasculitis (8).

Answers to some of these riddles might provide better guides for supportive care including clarification of the indication for use of corticosteroids. Steroids reduce the toxic manifestations and shorten the febrile course but whether they exert a fundamental beneficial influence is unknown.

Microbial Persistence and Recrudescence. Brill-Zinsser disease (recurrent epidemic typhus fever) is an excellent example of microbial persistence in the human host. It is likely but unrecognized that such recurrences occur in R.M.S.F. Q fever, murine and scrub typhus. It would be possible to follow patients convalescent from these diseases when they undergo stress such as during other illnesses or surgical procedures. A suspicious complicating mild febrile illness might be identified by serologic methods and in the instance of recurrence of R.M.S.F. a prompt high titer rise of 7-S antibody using the C.F. or M.A. technique would be confirmatory.

There is ample evidence of persistence of pathogenic R. prowazeki, R. rickettsii and R. tsutsugamushi in convalescence which have been isolated from lymph node tissue months to years after recovery from the initial illness. Conceivably, a rickettsicidal antibiotic other than chloramphenicol or tetracycline, which are rickettsiostatic, would eradicate such persisting rickettsiae. This is a minor problem.

REFERENCES
1. Brenzina, R., Murray, E.S., Tarizzo, M.L., Bogel, K. 51973) Rickettsiae and rickettsial disease. Bull. World Health Org., 49: 433-442.
2. Woodward, T.E. (1973) A historical account of the rickettsial diseases with a discussion of unsolved problems. The first Maxwell Finland Lecture. J. Inf. Dis. 127: 583-594.
3. Woodward, C.L., Woodward, T.E. (1975) Clinical case history by E.R. Squibb and Sons, Inc. Published by C.P.C. Communications, Inc., Greenwich, Conn.
4. DeShazo, R.D., Boyce, J.R., Osterman, J.V., Stephenson, E.H. (1976) Early diagnosis of Rocky Mountain spotted fever. Use of primary monocyte culture technique. J.A.M.A. 235: 1353-1355.
5. Pedersen, C.E., Bagley, L.R., Kenyon, R.H., Sammons, L.S., Burger, G.I.(1975) Demonstration Of Rickettsia rickettsii in the Rhesus monkey by immune fluorescence microscopy. J. Clin. Microbiol. 2: 121-125.
6. Woodward, T.E., Pedersen, C.E., Oster, C.N., Bagley, L.R., Romberger, J., Snyder, M.J. (1976) Prompt confirmation of Rocky Mountain spotted fever: Identification of rickettsiae in skin tissues. J. Inf. Dis. 134: 297.
7. Walker, D.F., Cain, B.G. (1978) A method of specific diagnosis of Rocky Mountain spotted fever on fixed, paraffinembedded tissue by immunofluorescence. J. Inf. Dis. (In press).
8. Mosher, D.F., Fine, D.P., Moe, J.R., Kenyon, R.H., Ruch, G.L. (1977) Studies of the coagulation and complement systems during experimental Rocky Mountain spotted fever in Rhesus monkeys. J. Inf. Dis. 135: 985-989.
DISCUSSION
M. Isaacson : You had one very severe case of generalized Schwarzman-like reaction in one of your Spotted Fever cases and we noted that the patient had been treated with steroids early on. Do you feel this may have in fact precipitated or aggravated the condition ?
T.E. Woodward : We do not think there is any connection. The only time we used steroids was in a very severely ill patient and the reason we used them is aimed at the brain oedema more than anything else. But in a number of patients, the diffuse haemorrhages occur without steroids, I don't think there is any connection. in a severely iZl patient, I would not hesitate one minute to give steroid on a short time basis. I don't think there is any evidence that one has influenced mortality, there is not enough information, but I am convinced that there is no deleterious sideeffect.
M. Isaacson : Why was chloramphenicol used in preference to tetracyclin ?
T.E. Woodward : No good reason, either one is perfectly acceptable. Tetracyclin can be given in lower dosage, but I have no real argument or point either way. We just happen to use chloramphenicol, we are well aware of what has been reported, we think that the side-effect is about 1140.000 but I quite agree with you tetracyclin is just as good.
A. Silberstein : Do you rely on the central venous pressure to determine the fluid input ? T.E. Woodward : None of the patients shown had central venous pressure measurements. I think careful monitoring, looking at skin turgor, and measuring pulse blood pressure are very useful.

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