CHAPTER II
Sandfly Fever
William A. Reilly, M.D., Roberto F. Escamilla, M.D., and Perrin H. Long, M.D.
The diagnosis of sandfly fever was not made as frequently as it should havebeen, because of an unfamiliarity with the disease and a certain reluctance onthe part of medical officers to make the diagnosis solely from the clinicalpicture.1
Sandfly fever, also known as Phlebotomus fever and pappataci fever, attainedimportance in Allied and Axis forces in the Mediterranean (formerly NorthAfrican) Theater of Operations, U.S. Army, in World War II by incapacitatinglarge numbers of men for periods of 7 to 14 days, or longer. This disease wasknown to be endemic in the Mediterranean littoral and was first recognized inU.S. forces in North Africa toward the end of April 1943. Although not reportedas such in the statistical health report (WD MD Form 86ab), the first patientswere seen at the 77th Evacuation Hospital then situated near B?ne, Algeria. Atthat time, typical cases were described, and a careful study was made of therelation and importance of meningeal irritation to the general findings in thedisease. The patients had come from the U.S. II Corps which was then engagedagainst the enemy in northern Tunisia. At the same time that these patients werebeing studied and the disease recognized in the 77th Evacuation Hospital, anincreased incidence of influenza was observed by the medical services of theother evacuation hospitals within the corps area and also a sharp increase inthe number of cases of F.U.O. (fever of undetermined origin) was noted in thestatistical health report for April 1943. While no careful search for sandflieswas conducted by trained entomologists during that period, it is known thatsandflies, Phlebotomus papatasii, were captured and identified as such innorthern Tunisia by certain British medical officers and by members of thehygiene section of the British First Army.
While knowledge concerning the incidence of sandfly fever in U.S. forces inNorth Africa during the summer of 1943 is obscured by the fact that thediagnosis was infrequently made and doubtlessly most of the cases wereclassified as F.U.O., the disease is known to have occurred frequently in theregion of Tunis, Mateur, Ferryville, and Bizerte in Tunisia; also
1Letter, Lt. Col. Perrin H. Long, MC, Consulting Physician, Office of the Surgeon, Headquarters, NATOUSA, to the Surgeon, NATOUSA, 24 Aug. 1943, subject: A Report Upon Medical Services in Sicily.
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around Oran and Algiers in Algeria.2Cases of the endemic disease were noted in members of the Allied forces inAlgiers and, in at least one instance, a fairly extensive outbreak occurredamong members of a signal corps detachment which was situated just outside thecity. In this outbreak, the disease was thought to be dengue until a review ofthe clinical findings in the disease revealed an absence of secondary rises infever. An entomological survey of the area of this detachment established thepresence of many sandflies of the variety P. papatasii.
A review of the plans for the amphibious operation in Sicily which dealt withthe professional services shows that sandfly fever was considered a likelythreat to manpower during the Battle of Sicily and that the peak of the diseasewould be reached after 1 August 1943. This prediction was more than realized,because the disease which had been contracted in North Africa began to make itsappearance on D-day in Sicily, and, while no cases of the disease were reportedin the statistical health report for NATOUSA (North African Theater ofOperations, U.S. Army) for July 1943, in reality, there were hundreds of casesof sandfly fever in the troops in Sicily during that month. This lack ofreporting was due to the diffidence that medical officers then showed in makingthe diagnosis of the disease from the clinical findings alone.3
Despite the reporting of but 104 cases, the disease reached epidemicproportions in Sicily because it was a favorable summer for the propagation ofsandflies, the type of fighting was from village to village, native habitationswere used as billets, and discipline in respect to the use of nets and insectrepellents was poor. Sampling studies made in division clearing companies andevacuation hospitals during the first 2 weeks in August produced clinicalevidence that, at a minimum, at least 25 percent of the cases diagnosed as F.U.O.should have been diagnosed as sandfly fever. During the latter half of the monthof August and the first half of September, this same percentage probablyprevailed.
The invasion of Italy by way of the beaches at Salerno (anarea in which sandflies were common) was attended by a large number of cases ofsandfly fever. This invasion was spearheaded by the 36th Infantry Divi-
2In May 1943, shortly after Von Armin's army was driven out of Tunis,contact was possible with U.S. Army Forces in the Middle East (Egypt) and thePersian Gulf Service Command (Iran-Iraq). Reports of the extensive outbreaks ofsandfly fever there, which occurred in U.S. personnel, were beginning to beavailable although it was apparent that in these areas, too, medical officerswere loath to make the diagnosis, preferring F.U.O. or influenza.
3An analysis of the possible extent of sandfly fever cases in the Siciliancampaign, nearly all of which were probably erroneously diagnosed as malaria orconservatively labeled F.U.O., was the subject of a special report made by Maj.(later Lt. Col.) Albert B. Sabin, MC, in September 1943. This report wassubsequently published in part by Major Sabin, Lt. Col. Cornelius B. Philip, MC,and Dr. John R. Paul. The conclusion reached by Major Sabin was that sandflyfever was probably responsible for as many, if not more, cases of fever asmalaria. (1. Letter, Maj. Albert B. Sabin, MC, to Chief Surgeon, Seventh Army:Col. Daniel Franklin, 7 Sept. 1943, subject: Estimate of Extent to Which SandflyFever Was and Is a Problem Among American Forces in Sicily. 2. Sabin, A. B.,Philip, C. B., and Paul, J. R.: Phlebotomus (Pappataci or Sandfly) Fever; ADisease of Military Importance: Summary of Existing Knowledge and PreliminaryReport of Original Investigations. J.A.M.A. 125: 603-606, 1 July 1944.)
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sion, a unit which had had little experience with sandflyfever and hence was comprised mainly of susceptible persons. Again, as inSicily, the troops made use of buildings both as strong points during thefighting and subsequently as billets, and discipline in the use of nets andrepellents was poor. Because of certain command difficulties, it was impossibleto have an adequate study made of the F.U.O. cases in Fifth U.S. Army hospitalsduring September and early October, so that an approximation of the number ofcases of sandfly fever was not made, although from the rather meager data athand it seemed probable that the incidence of the disease in the Fifth U.S. Armyduring this period was similar to that experienced by the Seventh U.S. Army inSicily.
In 1944, in Italy, the situation in respect to the diagnosis of sandfly feverwas considerably improved, and the figures for that year were much morerepresentative of the actual incidence of the disease than they were in 1943.However, it must be recorded that, even after an indoctrination campaign hadbeen conducted in the diagnosis of sandfly fever, there were many medicalofficers who, because a specific diagnostic test for this disease did not exist,preferred to make the diagnosis of F.U.O. Frequent examples of this failure tomake the proper diagnosis were encountered in the monthly essential technicalmedical data reports, in which medical officers, after having describedclassical examples of the disease, would state that although sandflies are knownto exist in this area, the fact that none of the patients had seen the insectsand few if any gave a history of having been bitten by sandflies, the diagnosisof sandfly fever could not be definitely established and that, hence, the caseswere classified as being F.U.O.
In MTOUSA (Mediterranean Theater of Operations, U.S. Army), during the winterof 1944 and spring of 1945, an intensive campaign of education was carried outin respect to the clinical findings in sandfly fever. The effect of thiscampaign became evident because the incidence of sandfly fever as reported inthe statistical health reports for May, June, and July, 1945, reflected the trueincidence of the disease.
While the literature upon disease in the Wehrmacht wasscanty, it was known that German troops based in the Mediterranean area sufferedfrom sandfly fever. Hallmann,4 in 1941, described an outbreak ofsandfly fever that occurred in German soldiers who were stationed in the islandsand the Greek mainland near Athens. The majority of the cases of the diseasewere seen in July and August, and it was estimated that 20 percent of all thetroops in the area had the disease during this time. In a report printed inBerlin in 1944,5 an analysis of 5,890,000 records for admissions tohospitals for sickness in the German Army from 1 September 1939 to 31 March 1943was made. Of the admissions recorded in this report, 1,062,920 were for
4 Hallman: Beitrag zum Pappatacifieber 1941 auf der Balkanhalbinsel. Deut. trop. Ztschr. 43: 64-68, 1 Feb. 1943.
5Die Infektionskrankheiten im jetzigen Kriege, Anlage zuDer Heeres-Sanit?tsinspekteur. Nr. 8715/44 geh. (Wi G) Pr?f Nr. 50. Berlin, den 28.8.1944.
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infectious diseases. Sandfly fever (Pappatacifieber) was 13thon the list as a cause for admission with 4,941 cases recorded without anydeaths and with an average period of hospitalization of 13.4 days. Inasmuch asthe Wehrmacht had a large number of troops stationed in the Mediterranean andBlack Sea littorals in 1941, 1942, and 1943, it is astounding that but 4,941cases of sandfly fever were recorded. It is especially surprising when oneconsiders that in this study no mention was made of the existence of F.U.O. Thetruth of the matter probably lies in the fact that during this same period atotal of 159,890 cases of "grippe" were recorded from hospitalreports. It is likely that many cases of sandfly fever were reported incorrectlyunder this diagnosis.
ETIOLOGY
It was established in 1908 by Doerr, Franz, and Taussig6that the causative agent of sandfly fever is a filterable virus and that themidge, P. papatasii, is the vector of this disease. This finding was confirmedby other observers7 and also by Sabin, Philip, and Paul. Sabin andPaul studied the disease in Sicily after the end of the Sicilian campaign in1943. As a result of their studies, they obtained the following informationregarding the virus of sandfly fever:
Virus is present in the blood of patients 24 hours before theonset of fever and during the first 24 hours thereafter; it is no longerdemonstrable 48 hours after onset. It may be passed serially in volunteers byparenteral inoculation although the intracutaneous and intravenous routes weremore effective than the intramuscular or subcutaneous routes. Attempts torecover virus from the spinal fluid obtained in the first 2 days of theexperimentally produced disease were unsuccessful. The virus survived in thefrozen state at Dry Ice box temperature or in the lyophilized state in anordinary refrigerator for 6 months. The size of the virus as determined byfiltration through gradocol membranes appeared to be not larger than 25 to 37 mμ, although the low titer of virus (1,000 minimum infectious doses per ml. ofserum) suggests the possibility that it might be even smaller. Unsuccessfulattempts were made to inject embryonated eggs and a wide variety of speciesincluding young baboons (Papio hamadryas) and monkeys of the followingspecies: grivet (Cercopithecus griseoviridis), vervet (Cercopithecusaethiops pygerythrus), red African hussar (Cercopithecus [Erythrocebus]patas), Macaca radiata and Macaca mulatta (rhesus). The rodentsincluded young white mice, wild gray mice, Syrian hamsters, Egyptian desert rats(jerboas), rabbits, guinea pigs, and cotton rats.
As cited by Warren and Johnson,8 Sabin also showed that there was morethan one strain of sandfly fever virus. Volunteers who had been inoculated
6Doerr, R., Franz, K., and Taussig, S.: Das Pappatacifieber. LeipzigundWien: Franz Deuticke, 1909.
7(1) Birt, C.: Phlebotomus Fever in Malta and Crete. J. Roy. Army M. Corps14: 236-258, 1910. (2) Birt, C.: Sandfly Fever in India. J. Roy. Army M. Corps15: 140-147, 1910. (3) Tedeschi, A., and Napolitani, M.: ExperimentelleUntersuchungen ?ber die Aetiologie des Sommerfiebers. Centralbl. F. Bakteriol.57: 208-211, 1911. (4) Shortt, H. E., Poole, L. T., and Stephens, E. D.: SandflyFever on the Indian Frontier; A Preliminary Note on Some LaboratoryInvestigations. J. Roy. Army M. Corps 63: 361, December 1934; and 64: 17,January 1935. (5) Shortt, H. E., Poole, L. T., and Stephens, E. D.: Note on SomeExperiments With Sandfly Fever Blood and Serum. Indian J.M. Research 23:279-284, July 1935. (6) Moshkovsky, Sh. D.: Studies on Pappataci-Fever. Med.Parasitol. and Parasitic Dis. Moscow 5 (No. 6): 823-862, 1936.
8Warren, R. O. Y., and Johnson, J. W., Jr.: Sandfly Fever in NATOUSA. M.Bull. Mediterranean Theat. Op. 3: 160-164, May 1945.
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with a strain of virus obtained from a patient in the firstday of his illness in Caserta, Italy, developed typical sandfly fever; they werenot subsequently protected by this attack against an inoculation with theSicilian strain of the virus.
EPIDEMIOLOGY
It is believed that P. papatasii is the chief vector of sandfly fever inNATOUSA. The adjacent shores and islands of the Mediterranean, Adriatic, andAegean Seas which were included in the North African and Mediterranean theatershave long been known as favorable breeding places for the moth midges of thegenus Phlebotomus. The hilly and rocky terrains of Algeria, Tunisia, Sicily,Sardinia, Corsica, and Italy and the adobe or stone houses which dot these areasgive rise to what was aptly called "the classical sandfly situation,"by Maj. Marshall Hertig, SnC. The female sandfly by choice seeks rocky places,cracks in masonry, buildings, stone walls, or rubble and caves in which to layits eggs; the adult midges seek outdoor shelter in caves, cracks in stones andbuildings, and under the eaves of buildings. A cool, shaded, slightly dampenvironment is ideal for the life of this insect.
Sandflies rest during the day and feed during the night. The female alonebites, an act which she performs persistently and viciously; a meal of blood isnecessary for proper ovulation (fig. 1).
The incidence curves of sandfly fever and F.U.O. in NATOUSA-MTOUSA fromJanuary 1943 to December 1945 are presented in chart 1. The first cases ofsandfly fever were reported in August 1943 although the disease was recognizedin North Africa as early as April 1943. In 1943, the peak monthly rate(September) was 7.9 per 1,000 per annum, a rate doubtlessly far below the actualrate, because the vast majority of cases of sandfly fever were reported as F.U.O.Since careful studies were not made upon any sample group of cases of F.U.O. in1943, there was little information about the correct diagnoses at the time ofthe final disposition of these patients, and it will never be known whatpercentage of patients diagnosed as having F.U.O. during the summer of 1943 werein reality suffering from sandfly fever. It is to be remembered, however, atthis point, that many cases of malaria were also classed as F.U.O. in 1943 andthat the total rate does not primarily represent undiagnosed cases of sandflyfever.
The incidence curve during 1944 more closely approximated thetrue incidence, since medical officers were beginning to have some familiaritywith the disease and hence were more prone to make the correct diagnosis. In aninteresting study of F.U.O.9 made by Maj. Emil C. Beyer, MC, it wasfound that a diagnosis of sandfly fever was made at the final disposition in 2.4percent of 450 cases initially undiagnosed upon admission as F.U.O. during themonths of June, July, and August, 1944. However, in this same group,
9Beyer, E. C.: Fever of Undetermined Origin. M. Bull. MediterraneanTheat. Op. 3: 208-209, June 1945.
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the diagnosis of F.U.O. or of febricula appeared in 8.4 and10.7 percent, respectively, of the final dispositions made during that period.Thus, the etiology of 19.1 percent of the patients having fever was in doubt atthe time of their final disposition, and it is possible that many of thosepatients may have had sandfly fever. That this is probable is evidenced by afurther study of the diagnoses which were recorded at the time of the finaldisposition of a similar group of patients, which was made by Major Beyer duringJanuary 1945. In this group only 8.9 percent were discharged with a finaldiagnosis of febricula or F.U.O. It is unknown how many times the originaldiagnosis of F.U.O. was changed to sandfly fever in the statistical healthreports, but on the basis of these figures, there is a possibility that about 10percent of the patients originally diagnosed as having F.U.O. in the summer andearly fall of 1944 had sandfly fever.
The incidence curve of sandfly fever for 1945 probablyrepresented the incidence of this disease quite accurately as the rates forF.U.O. were at low levels in comparison with corresponding months in 1943 and1944.
As will be noted from chart 1, cases of sandfly fever madetheir initial appearance in NATOUSA-MTOUSA in April and gradually built up to apeak in September; following this, there was a rapid decline within the next 2 months. Thus, the epidemiological pattern of the disease reflectedaccurately the life cycle of P. papatasii.
IMMUNITY
A natural resistance to sandfly fever apparently does not exist, and a largepercentage of susceptibles develop the disease if left unprotected in an
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endemic area. Livschitz10 reported that practically 100percent of experimentally inoculated volunteers who had had no previous contactwith the disease were found to be susceptible, while Sabin, Philip, and Paulstated that approximately 95 percent of their volunteers contracted the diseasefollowing their inoculation with virus. This same high rate of susceptibilitywas observed in U.S. forces when they were introduced into NATOUSA-MTOUSA, andinstances were recorded in which 80 percent of a command contracted the diseasein certain areas around Caserta. These observations were similar to those madeby Cullinan and Whittaker11 in the Middle East, where rates for sandfly feverof approximately 1,000 per 1,000 per annum or more were recorded in other ranksin two British general hospitals which had been located in areas in whichsandflies were abundant and in which sandfly fever was epidemic.
It was recognized also that second, third, or even moreattacks of sandfly fever could occur in the same individual and even the sameepidemic season. Livschitz observed that the initial rate of attack of thenatural infections in a group of 1,076 persons, who were newcomers in an endemicarea, was about 50 percent and that 22.8 percent and 0.9 percent, respectively,of 416 persons who had recovered from an initial infection had second and thirdattacks of the disease within the same epidemic season. Cullinan and Whittakerreported that 15 percent of the noncommissioned officers and other ranks in twoBritish general hospitals had second attacks (and some even third attacks) ofsandfly fever during a period of 3 months in which these men were exposed to thedisease in an epidemic area.
While there can be little doubt that an immunity to sandflyfever generally results from an attack of the disease, the observations whichhave just been recorded suggest that at times the immunity may not be solid. However, Sabin's investigations,12 previouslymentioned, indicated the existence of at least two different strains of virusand suggested the possibility that second attacks within the same epidemicseason or later may have been the result of an infection with a different strainof virus rather than waning immunity from the first attack.
CLINICAL COURSE AND DIAGNOSIS
Sandfly fever in NATOUSA-MTOUSA was characterized bythe sudden onset of fever, headache and severe retro-orbital pain, photophobia,generalized aching, malaise, and chilly and feverish sensations. Anorexia, nausea, and vomiting occurred in some patients. The face was suffused, theconjunctivas and scleras injected, and not infrequently pressure over theeyeballs caused pain. At times, a very faint pink erythema was present over
10Livschitz, J. M.: Studies on Pappataci Fever. Med. Parasitol. andParasitic Dis. Moscow 6 (No. 6): 938-943, 1937.
11Cullinan, E. R., and Whittaker, S. R. F.: Outbreak of Sandfly Fever in TwoGeneral Hospitals in the Middle East. Brit. M.J. 2: 543-545, 30 Oct. 1943.
12See footnote 8, p. 52.
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the shoulders and thorax, and the spleen was palpable in asmall percentage of patients. Many of the patients had relative bradycardia. Thefever lasted from 1 to 11 days, averaging 4 days, and was followed by a variableperiod of asthenia. In one large group of patients, the period ofhospitalization ranged from 1 to 25 days, averaging 6.2 days. Leukopenia waspresent in most cases at the time the patients entered the hospital with thelowest counts being recorded in the immediate postfebrile period. Thedifferential count was characterized by a relative or absolute increase in thelymphocytes (often with the appearance of large atypical forms) and an absoluteincrease in many patients in the younger types of the polymorphonuclear cells.
It is not unusual that the disease caused diagnosticdifficulties in medical installations in MTOUSA. In its milder aspects, itsimulated the milder forms of influenza. At times, the onset was similar to thatof malaria, infectious hepatitis, or primary atypical pneumonia, and itrequired much aid from the laboratory to differentiate promptly and accuratelybetween these diseases and sandfly fever.
On occasion, the occurrence of nuchal rigidity in patientswith signs and symptoms characteristic of sandfly fever made the differentialdiagnosis between this disease of aseptic meningitis difficult.13 Because of thelack of specific serological tests, the diagnosis of sandfly fever could not bemade in patients with evidence of meningeal irritation and pleocytosis of thespinal fluid, and it could not be proved that sandfly fever virus caused theaseptic meningitis syndrome. In experiments with volunteers, Sabin, Philip, andPaul did not believe that it occurred in any of 150 volunteers.
It is evident that, at times, the diagnosis of sandfly fever was difficultand that it required much clinical acumen and confirmation by the laboratory.However, too often in MTOUSA, the reluctance to make the diagnosis resulted fromintellectual slovenliness and from the ease with which, for diagnostic purposes,the disease could be classified as F.U.O.
TREATMENT AND PREVENTION
The treatment of sandfly fever in NATOUSA-MTOUSA was purely symptomatic intype.
It was found in NATOUSA-MTOUSA that theprevention of sandfly fever was dependent upon the precautions taken by theindividual against being bitten by sandflies and upon environmental controlmeasures aimed at the eradication of sandflies.
SUMMARY
Sandfly fever was a problem of great importance to the U.S.Army in NATOUSA-MTOUSA, and it was responsible for much loss of manpower duringthe summers of 1943 and 1944.
13See footnote 8, p. 52.
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Due to the variations in the clinical picture of sandfly fever, and becausespecific tests for establishing its identity were not available, medicalofficers were often reluctant to make the diagnosis of this disease on the basisof their clinical findings. As a result, many thousands of cases of sandflyfever were probably recorded as F.U.O., and hence, the data recorded in thestatistical health reports from NATOUSA-MTOUSA regarding this disease wereinaccurate.
Sandfly fever could have been prevented in the areas in which the disease wasendemic if the proper individual precautions for the prevention of this diseasehad been observed and if a program for the environmental control of sandfliesbased upon the use of DDT (dichlorodiphenyltrichloroethane) sprays had beeninstituted.
