Typhus fever has afflicted mankind since ancient times. Although the plague of Athens in 430 B.C. is believed to have been epidemic typhus (MacArthur, 1954), the account of Fractiousness in 1546 is the earliest medical record that describes typhus fever with sufficient accuracy to permit its definite identification. Despite the work of Fracastorius, typhoid and typhus fevers were usually regarded as one entity byphysicians until 1837, when Gerhard in Philadelphia clearly differentiated the two disorders on the basis of the important clinical and pathologic differences. Even today, however, confusion in terminology persists in those parts of Europe where typhoid fever is called “typhus abdominalis.”
Typhus fever has played a major role in the history of the past four centuries. It followed in the wake of wars, famines, and human misfortunes. It often has had a more decisive effect on military campaigns than the actual battles themselves, a subject admirably treated by Zinsser in his book, Rats, Lice and History. Typhus epidemics in eastern Europje and Russia between 1918 and 1922 are estimated to have caused 30,000,000 cases and at least 3,000,000 deaths. Millions of,’cases occurred again during World War II in Nazi prison camps, in the Eastern European combat zone, among Yugoslav partisan forces, and in North Africa.
In 1916 da Rocha Lima showed that typhus was caused by the micro-organism that he named Rickettsia prowazeki. This organism has a protean morphology with coccobacillary forms predominating. However, the most typical form is a diplobacillus which has slightly pointed ends with a transparent band between the two bacilli. The organism takes on a characteristic red color when stained by the Gimenez method. R. prowazeki possesses a soluble antigenic moiety which is shared also by Rickettsia mooseri, the other member of the typhus group.
R. prowazeki is readily killed by common antiseptics and dies in a few hours if exposed to room temperature- It remains viable for several days in blood at +5° C. Hence, a specimen of blood from a suspected case of typhus can be held for a day or more in a refrigerator pending isolation procedures. Organisms remain viable for several months in dried louse feces, and have survived.for over 20 years when quick-frozen in an alcohol bath and stored at —60° C.
Living R. prowazeki organisms contain a toxin that is lethal for mice as well as a substance that is hemolytic for the red blood cells of many animals.
The role of the human body louse in the transmission of typhus was first demonstrated experimentally by Nicolle, Comte, and Conseil in 1909. A few years later mechanisms of transmission were precisely worked out by Wol-bach, Todd, and Palfrey (1922) in their classic experiments in Poland on the etiology of typhus fever.Man and the louse are the only known natural hosts of R. prowazeki. There is no passage of R. prowazeki organisms from one louse vector generation to the next via the egg. Furthermore, there is no confirmed evidence as yet of an animal reservoir.
The chain of typhus infection starts when R. prowazeki appears in a patient’s blood during the febrile period. A louse becomes infected during one of his frequent blood meals. The rickettsiae multiply in the cells lining the gut of the infected louse. First these cells become greatly distended and then burst, discharging myriads of micro-organisms into the gut where they inyade other lining cells or pass out in the feces.
The disease is invariably fatal to the louse owing to the ultimate complete (iestraciiDH & iss* epithelium. Transmission of rickettsiae from aninfected louse to a new human host can occur by several mechanisms. When a louse takes a blood meal, it makes a small puncture wound in the skin, defecating at the same time.
The louse bite is irritating, causing the patient tc scratch and thus rub infected feces into the wound. I: Is also possible for one to become infected if dried infected louse feces gain access to the mucous membranes of the eye or respiratory tract. In an epidemic the spread of typhus from patient tc parent and community to community is clearly related to the temperature preferences of the louse. Lice ir.oose a 29° C. environment which they find in the folds oi Vrife gaxisveHte stealthy man.
Here they live and lay their eggs. Lice tend to leave a typhus patient when his temperature rises to 104: F. or higher. Also, they quickly abandon a corpse in search of a warm host. Transmission of typhus from man to man occurs only bv means of the louse; hence, once deloused and bathed, a typhus patient cannot transmit the disease
The microscopic path d logy of typhus is characteristic. Rickettsiae multiply in the endothelial cells lining the small blood vessels. Endothelial proliferation and perivascular infiltration lead to thrombosis and leakage. Such vascular lesions when they occur in the skin produce the rash, whereas lesions in the meninges most probably account for the highly characteristic rickettsial headache. The myocardium is also a frequent focus of vascular lesions. Gangrene is directly related to thrombosis of capillaries, small arteries, and veins in affected areas (McAllister).
Clinical Manifestations and Course.
The incubation period is approximately ten days to two weeks. Prodromata of vague malaise and headache are not uncommon, especially in vaccinated individuals. The onset is usually abrupt, and the patient can frequently state the exact hour when his illness began. The major clinical signs and symptoms are fever, headache, and rash. The fever may rise to 102 to 104° F. (39 to 40° C.) the first day, or it may take two or three days to reach this level. However, once the temperature reaches 104° F. (40° C.) it tends to remain at this level or higher with only slight fluctuations until altered by treatment or recovery. A remittent (or widely fluctuating) temperature is not characteristic of untreated typhus except very late in the disease or in vaccinated persons.
The headache is characteristic.
It is intense, persists night and day, and is intractable to all efforts at alleviation. The rash makes its appearance on the fourth to seventh day of illness and consists at first of pinkish macules that fade on slight pressure. These discrete macules usually appear first on the upper trunk in the axillary area. In the course of one or two days the rash spreads over the entire body, usually sparing the face, palms, and soles which are involved only rarely. The macules soon become darker, fixed, and maculcpapular. In severely ill patients the rash may progress to petechial, hemorrhagic, or conftuem forms.
Patients often have a slight cough without sputum as in mycoplasmal pneumonia. An accompanying patchy pulmonary consolidation is more often diagnosed roentgenographically than by physical examination. Respirations may be increased out of all proportion to findings in the chest.At first the pulse rate is slow in relation to the temperature, but by the end of the first week it becomes rapid (110 to 140 . weak, and frequently undulating or irregular.
The blood pressure is usually low, and there may be brief episodes of severe hypotension. Conjunctivitis and flushing of the face are frequent findings. The spleen is palpable in about half the cases. Renal insufficiency of varying degree is a common occurrence. During the acute phase, deafness and ringing in the ears are common complaints, as is also myalgia of the back and legs..
In fatal cases the terminal period is usually characterized by a profound smpor. peripheral vascular collapse, and severe renal failure. In cases without complications, the temperature begins to drop rapidly by lysis between the thirteenth and sixteenth days of illness. Recovery of normal mental and physical powers is remarkably rapid, although the patient may no: r regain his full strength for two to three months.
Typhus Fever in Previously Immunized Persons.
The symptoms and clinical course of typhus are greatly modified as a consequence of prior active immunization. The illness may consist merely of a mild headache and fever of several days’ duration. Most patients, however, go on to develop a transient oracular rash and suffer from a relatively severe headache and fever for about a week. Complications are rare; mortality has not been reported, and the diagnosis can .be established only by serologic or isolation studies.
Typhus Fever Modified by Specific Treatment.
If specific treatment. is begun early, the clinical course of typhus is usually arrested at whatever stage is present when treatment begins. The temperature usually drops to normal within 36 to 72 hours, and the- major clinical signs and symptoms (including’ the rash) disappear soon there-after. However, weakness of a greater or lesser extent almost always persists for days or weeks after recovery. On the other hand, if the disease is allowed to progress untreated beyond the eighth or ninth day, treatment becomes less and less effective. In such cases clinical recovery will depend largely upon the extent of vascular damage produced in the heart, brain, and kidneys before therapy was begun.
Clinical Diagnosis of Typhus Fever.
Before the characteristic rash appears, it is impossible to assert on clinical grounds alone that a patient is suffering from epidemic typhus. The early stages of a number of acute infectious diseases closely resemble the first few days of epidemic typhus —for example, smallpox, relapsing fever, malaria, typhoid fever, meningococcal infection, yellow fever, and several of the other rickettsial diseases. Of major help in the differential diagnosis is the characteristic macu\opapu\ax typhus rash that begins on the upper trunk and extends centrifugally to the extremities. The rash may be evanescent in children as well as in mildly ill adults. It is also difficult to recognize in dark-skinned subjects.
Laboratory Diagnosis. Specific Serologic Tests.
Complement-fixing antibodies first appear in the serum of patients between the seventh and twelfth days of the disease. Soluble antigens that are commercially available detect group antibodies common to both murine and epidemic typhus. In most instances epidemiologic considerations such as geographic location and type of vector involved (flea or louse) will suffice to distinguish between these two diseases in the typhus group. When confusion in diagnosis arises, specific washed antigens (available in special rickettsial laboratories) can be used to differentiate between murine and epidemic typhus. In performing the complement-fixation test it is important to use 4 to 8 units of either type of antigen employed in order to detect the early IgM type of antibodies.
Other special serologic tests that can be used in laboratory diagnosis include immunofluorescence, mouse toxin neutralization, and rickettsial agglutination. Agglutination can also be carried out using sheep or human group O erythrocytes sensitized with a serologically active fraction derived from rickettsiae treated with ether, heat, and alkali (erythrocyte-sensitizing substance or ESS — Chang). These special tests are available in rickettsial research laboratories, but are rarely if ever needed to establish a diagnosis.
Persons recovered from typhus may show significant antibody titers in their sera for months or years after an attack of the disease. Hence for definitive diagnosis it is important to demonstrate a rise or fall in antibody titer related to the acute or convalescent period of the clinical disease.
The Weil-Felix reaction, although nonspecific, is of great value in indicating the strong probability of a typhus infection. The test is positive in over 90 per cent of bona fee cases of. primary epidemic typhus. The bails for the Weil-Felix reaction is related to the fact that a certain antigenic component found in rickettsiaeis shared by some strains of Proteus vulgaris. Thus R. prowazeki can stimulate antibodies that will agglutinate the OX-19 strain of Proteus. Since low levels of Proteus OX-19 antibody are present in many healthy individuals, diagnostic significance is only attached to titers of 1 to 160 or greater.
Such titers are usually demonstrable between the seventh’ and eleventh days after onset of typhus. The rapid slide method which can be carried out in only three to five minutes is quite satisfactory when performed with controls. Occasionally agglutinins develop for the OX-2 Proteus strains but none for OX-K. Proteus OX-19 antibody titers also develop in other rickettsial diseases, notably murine typhus and Rocky Mountain spotted fever.
Isolation of Rickettsiae from the Patient.
The laboratory diagnosis of typhus may be made by inoculating blood from a patient into a susceptible species such as the guinea pig or chick embryo if facilities are available for the further manipulations required to establish the identity of the micro-organisms thus obtained.
The prognosis in untreated cases is closely correlated with age. In children under ten years the disease is usually mild, and fatalities are uncommon. In adults the mortality ranges from 10 per cent in the second and third decades of life to more than 60 per cent in those over 50. However, active immunization and the use of specific therapy greatly affect mortality figures.
In the absence of specific treatment, the appearance of renal insufficiency is an early sign that a patient’s illness will be severe or fatal. The extent and severity of the typhus rash is also roughly indicative of the severity of the disease. Complications such as pneumonia or gangrene of the skin are likewise serious prognostic signs.
A fall in systolic blood pressure to values below 80 mm. of mercury for a few hours or longer may cause damage from which the patient may not recover, even though the blood pressure rises after the period of severe hypotension.
Chloramphenicol or the tetracyclines are highly effective when given early and in adequate dosage. The clinician must decide on the basis of his own preference which drug he will use. Recent reports suggest that doxycycline is also an effective drug in the treatment of rickettsial infections.and recuperative powers are major factors .in his recovery.
Prevention of Typhus Fever;.
Two highly effective measures, immunization and louse control, are available for the prevention and control of typhus. Both are applicable to an individual as well as a community. For immunization, there are commercially available killed typhus vaccines produced from yolk sacs of infected chick embryos. Immunization with killed vaccines does not fully protect against infection. However, when vaccinated individuals do contract typhus, the course of illness is shorter and milder, and fatalities have not been reported. An experimental living attenuated “Strain E” typhus vaccine is under trial in the United States, the USSR, and Africa. Moderately severe illness has occurred in a small percentage of those inoculated with minimal immunizing doses of this vaccine.