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Chapter V

Contents

CHAPTER V

Q Fever

Charles A. Ragan, Jr., M.D.

OCCURRENCE

Q fever first appeared among Allied troops in 1944 and 1945 when several sharp outbreaks occurred in the Mediterranean (formerly North African) Theater of Operations, U.S. Army.1 That it was not identified immediately was doubtless related to the fact that this rickettsial disease had first been described in 1937,2 and that, with the exception of laboratory infections,3 the disease had been reported only from Queensland, Australia, as occurring naturally in human beings. The author was present as Chief, Medical Service, 15th Field Hospital in Italy, when some of the first military patients were seen, and it must be confessed that there was no realization at that time that an unusual situation was developing. In retrospect, it is of interest to reflect upon the interplay of serendipity, error (a single positive Weil-Felix reaction), and the presence of Maj. Frederick C. Robbins, MC, in Naples that led to the realization that we were dealing, not with common primary atypical pneumonia, but with Q fever, appearing naturally in a locality far distant from Queensland. Subsequently, the disease was recognized in southern Italy, Greece, and Panama. Since World War II, Q fever has been recognized in California.4

Apennines outbreaks-The 15th Field Hospital was set up in December 1944 as a three-platoon unit acting as a medical evacuation unit behind the U.S. II Corps in the Apennines north of Florence. The hospital was studying the feasibility of early return to duty of patients with various psychosomatic problems related to combat fatigue. In addition to such patients, there were others with trenchfoot, infectious hepatitis, and primary atypical pneumonia.

1Unless otherwise noted, the material presented in this chapter was taken mainly from a series of articles which appeared in the American Journal of Hygiene, volume 44, July 1946, pp. 1-182.
2(1) Derrick, E. H.: "Q" Fever, A New Fever Entity; Clinical Features, Diagnosis and Laboratory Investigation. M.J. Australia 2: 281-299, 21 Aug. 1937. (2) Burnet, F. M., and Freeman, M.: Experimental Studies on the Virus of "Q" Fever. M.J. Australia 2: 299-305, 21 Aug. 1937.
3(1) Cox, H. R.: A Filter-Passing Infectious Agent Isolated From Ticks. III. Description of Organism and Cultivation Experiments. Pub. Health Rep. 53: 2270-2276, 30 Dec. 1938. (2) Dyer, R. E.: A Filter-Passing Infectious Agent Isolated From Ticks. IV. Human Infection. Pub. Health Rep. 53: 2277-2282, 30 Dec. 1938. (3) Hornibrook, J. W., and Nelson, K. R.: An Institutional Outbreak of Pneumonitis. I. Epidemiological and Clinical Studies. Pub. Health Rep. 55: 1936-1944, 25 Oct. 1940. (4) Dyer, R. E., Topping, N. H., and Bengtson, I. A.: An Institutional Outbreak of Pneumonitis. II. Isolation and Identification of Causative Agent. Pub. Health Rep. 55: 1945-1954, 25 Oct. 1940. (5) Lillie, R. D., Perrin, T. L., and Armstrong, C.: An Institutional Outbreak of Pneumonitis. III. Histopathology in Man and Rhesus Monkeys in the Pneumonitis Due To the Virus of "Q" Fever. Pub. Health Rep. 56: 149-155, 24 Jan. 1941.
4Clark, W. H., Lennette, E. H., and Meiklejohn, G.: Q Fever in California. III. Aureomycin in the Therapy of Q fever. A.M.A. Arch. Int. Med. 87: 204-217, February 1951.


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Radiological facilities under the direction of Capt. Stanley M. Wyman, MC, were excellent.

In late February 1945, an officer from Headquarters Company, 339th Infantry, was admitted with high fever and general malaise without localizing symptoms, a picture suggesting the preicteric phase of infectious hepatitis. A roentgenogram of the chest at admission was interpreted as normal. A macular erythematous rash appeared transiently, and typhus was then considered in differential diagnosis, because several of the medical officers in the 15th Field Hospital had had duty in North Africa and had seen the disease in native populations. For this reason, a Weil-Felix test was done and was reported as positive in a significantly high titer from the 2d Medical Laboratory in Florence. Shortly thereafter, a second roentgenogram of the chest revealed an area of pneumonic consolidation, and a presumptive diagnosis of primary atypical pneumonia was made.

Within the next month, 32 additional members of Headquarters Company, 339th Infantry, were admitted with febrile illness, and 20 more patients from this unit were seen in other Fifth U.S. Army hospitals with similar symptoms. Major Robbins of the 15th Medical General Laboratory in Naples came to investigate the reported positive Weil-Felix reaction. From the blood of one of the patients with pneumonitis, a strain of rickettsia characterized as Rickettsia burneti was isolated by inoculation into guinea pigs and subsequent transfer to chick embryo yolk sac. This was established as the Henzerling strain. Sera were obtained from 28 patients during acute illness and convalescence, and convalescent samples were obtained from 25 other patients. Complement-fixing antibodies to the Henzerling strain were found in the sera of all 53 patients.

A second outbreak, originating in the same vicinity, was observed in April 1945 in the 3d Battalion, 362d Infantry, involving 267 patients of whom 80 were personally observed in the 15th Field Hospital. Sera of the acute disease and convalescence were obtained from 29 unselected cases, and a rising titer of complement-fixing antibodies to the Henzerling strain was demonstrated. The Paige strain of R. burneti was isolated from one patient in this group. In this epidemic, 70 percent of the patients not personally observed were reported as having atypical pneumonia or pneumonitis, and the remainder had diagnoses of fever of undetermined origin, infectious hepatitis without jaundice, or upper respiratory infection. Occasionally, no final diagnosis was made.

In a survey carried out by Major Robbins, Lt. Col. Ross L. Gauld, MC, and Capt. (later Maj.) Frank B. Warner, MC, several localities appear to be epidemiologically implicated in the high incidence of disease seen in these two outbreaks. Insects in the presumed areas of infection were numerous but no specific rickettsial vectors were discovered and the spraying of DDT (dichlorodiphenyltrichloroethane) did not modify the pattern of the outbreak in the 339th Infantry. An incubation period varying from 14 to


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26 days, with a peak at 19 to 20 days, was suggested by this epidemic. No cases developed in medical personnel caring for these patients. It was noted that the implicated areas were dusty, but no attempt was made to recover the reckettsia from dust. Rickettsia was successfully recovered from dust in California by DeLay, Lennette, and DeOme in 1950.5 High complement-fixing antibody titers to the Henzerling strain were found in a group of civilians from the epidemic area. Several other outbreaks, which were similar in their clinical and epidemiological features but not proved serologically, occurred in small units in northern Italy and Corsica. All outbreaks seemed to be related to dusty habitations.

Laboratory outbreaks-In June, July, and August, 1945, a laboratory outbreak of 20 cases developed in the 15th Medical General Laboratory in Naples. This epidemic was well documented by Major Robbins and was shown to have originated in the room of the laboratory where the Henzerling and Paige strains were being studied in guinea pigs and embryonate hens' eggs. The Seale strain of R. burneti was isolated in this epidemic, and rickettsiae were isolated from 16 of the 20 patients as early as the second day of disease and as late as the eighth. Complement-fixing antibodies to the Henzerling strain of rickettsia were absent in sera taken before the 7th to the 13th day of disease but were present with later specimens. The peak of the antibody response was reached on about the 21st day with a tendency to diminish after the 30th day. The disease contracted in the laboratory appeared to be somewhat more severe than that seen in the field, possibly owing to a greater initial exposure to the infectious agent; however, four patients, proved to be harboring rickettsia and sick with fever and malaise, developed no roentgenologic evidence of pneumonia.

Outbreaks originating in Greece-During the outbreaks north of Florence, it was learned that an epidemic of 40 cases of pneumonitis had appeared in one company of a battalion of British paratroopers who had come to Rome, Italy, from Athens, Greece, in January 1945. The outbreak appeared to have developed in Athens, and the men recalled exposure to dust in an abandoned silk mill used as a bivouac. Dr. J. Caminopétros of the Pasteur Institute in Athens had obtained from the blood of patients with "Balkan grippe" an agent producing a transmissible febrile disease in guinea pigs. Guinea pig blood was sent by him to the Commission on Acute Respiratory Diseases, Army Epidemiological Board (Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army), and from this, a rickettsia strain similar to R. burneti was isolated at the Commission laboratories at Fort Bragg, N.C. A laboratory outbreak caused by the "Balkan grippe" strain of Q fever occurred in the personnel in this laboratory before the rickettsia had been definitely characterized from the material sent from Greece. As was so often the case with these epidemics of

5DeLay, P. D., Lennette, E. H., and DeOme, K. B.: Q Fever in California. II. The Recovery of Coxiella Burneti from Naturally-Infected Air-Borne Dust. J. Immunol. 65: 211-220, August 1950.


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Q fever, the diagnosis was made in retrospect. Convalescent serum obtained from 35 of the British paratroopers who had been sick in Athens and Rome and sera from 43 well soldiers of the same battalion were tested for agglutinating antibodies to the "Balkan grippe" strain at Fort Bragg. Significant elevations were found in 29 of the 35 recovered cases, while only 9 of 43 men who had not been ill showed a high titer. Presumably, therefore, the epidemic in British paratroopers represented an infection with the "Balkan grippe" strain contracted in Athens.

Outbreak in Zone of Interior-An outbreak of Q fever was observed at Camp Patrick Henry, Va., in May and June 1945, after approximately 7,500 troops returning from southern Italy had disembarked. The disease was apparently confined to five squadrons of an air force group. Careful case finding in one squadron revealed 143 patients-an attack rate of 38 percent. Agglutinating antibodies to the "Balkan grippe" strain of R. burnetti were found, as were complement-fixing antibodies to the Australian strain, but no organism was isolated. The outbreak seemed to be related to a particular bivouac area, at Grottaglie Air Base near Taranto in southern Italy. Again, no cases developed in medical personnel caring for these patients.

Other outbreaks-A single case of pneumonia was studied in Panama from which a strain of rickettsia similar to R. burneti was isolated. The British Army in 1944 had observed in the Mediterranean area several sharply localized epidemics of "atypical pneumonia" characterized by a high attack rate-up to 50 percent of a unit. These may have represented Q fever, but no serological proof for this was obtained.

CLINICAL FEATURES

Mode of onset-In northern Italy, the disease was characteristically sudden in onset and the exact hour was frequently known. At Camp Patrick Henry, in contrast, 70 percent of the patients noted a gradual onset. These, however, represented the milder cases discovered by careful case-finding studies and would not have been observed in the Apennines epidemic in which only patients with complaints sufficient to require hospitalization were seen. The early symptoms were nonspecific-chilliness, sweats, general malaise, weakness, fatigue, muscular aches, frontal headache, and anorexia. Pain in the chest when present was variable in intensity, ranging from a vague to a definitely pleuritic character.

Symptoms.-Although the onset was usually sudden, it was seldom severe enough to cause prostration, and the patient often continued duty for 12 to 72 hours. The nonspecific symptoms persisted and became more pronounced with the ensuing rise in temperature. Frank rigor was seldom experienced. Frontal headache was common and severe, as in many rickettsial diseases, and a majority of the patients complained of retro-orbital pain aggravated by coughing. Anorexia was the only common gastrointestinal symptom. A moderately dry cough frequently developed on the fifth or sixth day but was


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not an outstanding feature. Approximately 20 percent of the patients who were carefully observed raised small amounts of blood-streaked sputum. Vague pain in the chest of the type described at the onset persisted, but true pleuritic pain was not common and was rarely severe, responding to aspirin and codeine therapy.

Physical findings-Temperature on admission ranged between 101° and 105° F. The curve was irregular, extremely sensitive in a transient fashion to salicylates, and persisted from 4 to 15 days. It returned to normal by lysis with an occasional crisis. Slight relative bradycardia, normal respiratory rate, and absence of cyanosis and dyspnea were usual. A cutaneous rash was seen only in the first patient. Physical findings in the chest were normal or only minimally altered. Crepitant rales and slight diminution of breath sounds or dullness were occasionally noted, after the roentgenogram called attention to abnormalities. Coryza and pharyngitis were not encountered although vesicles on the pharyngeal mucuous membrane were noted in the epidemic in British paratroopers. Splenomegaly was rare save in the British paratroopers who also had generalized glandular enlargement. Herpes simplex was not observed. Nuchal rigidity of moderate intensity was seen occasionally, but in six patients, lumbar punctures yielded normal spinal fluid. Guinea pigs inoculated with one of these fluids obtained from a patient in the Apennines outbreak had a transmissible disease, but serological proof for its rickettsial origin, that is, cross-immunity, was not obtained.

Roentgenological findings-The pneumonic infiltration as seen in roentgenograms was characteristic. Its incidence in all the outbreaks was not determined, but 80 percent of the proved cases in the Naples laboratory outbreak and 90 percent of those at Camp Patrick Henry showed such infiltration. The shadows were homogeneous, of a ground glass appearance and patchy in distribution, involving only a small portion of a lobe. Atelectasis with shift of an interlobar septum was frequently seen. In Italy, in most instances, lesions of a single lobe were observed, but occasionally, two lobes were affected. At Camp Patrick Henry, 60 percent of the patients had multilobar involvement. Lower lobe involvement predominated. There was no correlation between the extent of involvement demonstrated by roentgenogram and the severity of the disease. The roentgenogram of the chest on admission was frequently clear, with shadows appearing on the third or fourth, and occasionally as late as the sixth, day of the disease. Shadows consistent with small amounts of pleural fluid were seen in approximately 10 percent of the patients. The roentgenographic changes tended to be persistent and, frequently, were still present when the patient was discharged after an average stay of 22 days in the hospital. Resolution occurred by a gradual clearing of the involved area.

Course and convalescence-With defervescence, the symptoms rapidly subsided leaving only weakness, which varied with the severity of the disease. The duration of asthenia ranged from a day to 3 weeks. Loss in weight


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commensurate with a febrile illness associated with anorexia was usually observed. No deaths, no recurrences, and only one possible complication were seen in military personnel. The complication was a severe esophagitis in one patient in the Naples laboratory outbreak. The great majority of patients returned promptly to full duty.

Laboratory findings-Increase in numbers of leukocytes, polymorphonuclear leukocytosis, and anemia were not observed. The urine was normal except for occasional mild albuminuria at the height of fever. The erythrocyte sedimentation rate was moderately rapid during the acute phase of illness and became normal promptly after recovery. Blood cultures were sterile; enteric agglutinations, Proteus OX-19, OX-2, and OX-K agglutination (save in the original Apennines patient), coccidioidin skin tests, and throat cultures were negative. Cold agglutinins, antibodies to influenza A and B, treatment with the sulfonamides or penicillin were noted.

Treatment.-Treatment was symptomatic, and no beneficial effects of treatment with the sulfonamides or penicillin were noted.

EPIDEMIOLOGY

The Henzerling strain isolated in Italy, the "Balkan grippe" strain from Greece, and the strains isolated in the laboratory outbreak at Fort Bragg and in Panama were similar in immunological specificity (complete reciprocal cross-immunity) to the rickettsia isolated by Dyer6 (the American strain) although there were great variations in the sensitivity of the antigens. Cross-immunity between the Australian7 and American strains had previously been demonstrated. It therefore seems reasonable to assume that the rickettsial disease seen in the Mediterranean area and in Panama characterized by pneumonitis was Q fever. The relationship of Q fever to the usual form of primary atypical pneumonia was investigated serologically, and it was found to be close in endemic areas such as Caserta, Italy, but not in nonendemic areas such as the Eastern United States.

Mode of transmission-In the original cases from Australia, pneumonitis was not mentioned. The disease, there, is tickborne to cattle with a reservoir in bandicoots. The infection in man is aberrant, and the Australian workers postulated that the inhalation of dried tick feces present on the hides of cattle was the route of infection in human disease. Pneumonitis was first recognized in the laboratory epidemic at the National Institute of Health, U.S. Public Health Service,8 and in retrospect, it appears that this was probably a dustborne rickettsial infection. No insect vectors were implicated in the Italian or Greek disease, but dusty habitations were noted. Retrospectively, in view of the isolation of rickettsiae from dust in California,9 it

6See footnote 3, (2), p. 103.
7See footnote 2 (2), p. 103.
8See footnote 3 (3), p. 103.
9See footnote 5, p. 105.


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seems fair to assume that pneumonic Q fever may represent an infection in which the pulmonary infiltrate represents the primary lesion, as does the eschar in fièvre boutonneuse and rickettsialpox.

Military significance-The military implications of this disease can be far-reaching. It occurs in sharp outbreaks and, although rarely fatal, can completely incapacitate an entire unit for combat. A satisfactory form of prophylaxis was not at hand during the war years. Since World War II, it has been shown that oxytetracycline (Terramycin) and chlortetracycline (Aureomycin) are effective in the treatment of Q fever.10 The avoidance of dusty bivouacs in habitations where sheep, goats, or cattle have been kept may help, and disturbing of such dust by vigorous procedures should particularly be avoided.

10(1) Stokes, M. G. P.: Q Fever in Britain. Brit. M. Bull. 9: 231-233, 1953. (2) See footnote 4, p. 103.

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