# Tropical Diseases/Chapter 21

CHAPTER XXI
UNDULANT FEVER
FEBRIS UNDULANS, MALTA FEVER, MEDITERRANEAN FEVER
Definition.— Undulant fever— a disease of low mortality, indefinite duration, and irregular course —is the result of infection by a specific germ, the Micrococcus melitensis. In its more typical form it is made up of a series of febrile attacks, each individual attack, after lasting one or more weeks, gradually subsiding into a period of absolute or relative apyrexia, also of uncertain duration. Common and characteristic complications are rheumatic-like affection of joints, profuse diaphoresis, anaemia, liability to orchitis and neuralgia.
Geographical distribution.— Undulant fever was somewhat unfortunately named Malta fever, for we now know that the disease which was so designated is not, as was formerly supposed, confined to Malta, or even to the Mediterranean. It is very common there, particularly in Malta and the eastern and southern littoral of the Mediterranean; but recent investigations show that it occurs in Italy, France, Spain, the Red Sea littoral, India, China, South Africa, Somaliland, West Africa, the West Indies, the Brazils, the United States, and even in England. I have seen two cases which originated in England; they gave the serum reaction.* It is highly prob​able, therefore, that the same, or a similar, fever occurs in many other parts of the world, haring been confounded hitherto with malarial fever or with typhoid. This conviction is based rather on clinical than on laboratory observation.
As it is extremely prevalent at times in the Mediterranean fleet and in the garrisons of Gibraltar and Malta, this disease is specially interesting to naval and military surgeons. Although only occasionally proving fatal, it is a fruitful source of inefficiency and invaliding.
Until recently it appeared to be on the increase in its old haunts, and to be becoming common in places where it was formerly rare Port Said and Egypt, for example.
The following figures, supplied by Bassett-Smith, show its importance formerly to our Naval and Military Services in the Mediterranean:—
INCIDENCE OF UNDULANT FEVER
| | ARMY | ARMY | ARMY | NAVY | NAVY | NAVY | Total days |
| Year. | Strength | Cases. | Deaths. | Strength. | Cases. | Deaths. | sickness. |
| 1900 | 9,203 | 171 | 10 | 14,250 | 356 | 6 | 22,998 |
| 1901 | 9,384 | 288 | 10 | 14,070 | 286 | 3 | 16,987 |
| 1902 | 10,889 | 198 | 10 | 18,470 | 436 | 3 | 27,432 |
| 1903 | 10,608 | 507 | 11 | 18,410 | 400 | 6 | 30,541 |
| 1904 | 10,615 | 429 | 15 | 19,590 | 430 | 9 | 28,458 |
History.— Formerly undulant fever was confounded with typhoid and malaria. The labours of clinical observers from Marston (1861) to Maclean (1885), and more especially the bacteriological researches of Bruce (1887), Hughes, Gipps, Wright, Semple, and Bassett-Smith, have established it as a special disease. More recently an important advance of great practical value has been made by a Royal Society Commission, which has shown that the germ of this fever infests several of the lower animals, especially goats, in whose milk and urine it is excreted.
trustworthy. (This was written before the discovery of M. paramelitensis; it may be that the appropriate test was made with the wrong strain of micrococcus, and hence the discrepancy in the results. ) Lately, complement-fixation tests have given good results in Bassett-Smith's hands. ​Etiology.— Bruce, in 1887, demonstrated the presence in the spleen in undulant fever of a special bacterium the— Micrococcus melitensis— and by a series of experiments proved that it was the cause of the disease. Unfortunately the bacterium occurs only sparsely in the general circulation (unless in the earlier stages, when the temperature is high), and therefore to search for it in the later stages of the disease does not aid in diagnosis; but pathologically Bruce's discovery is of great importance, as it enables us to say positively that undulant fever is a distinct disease, altogether different from either typhoid or malaria. The organism is present in abundance in the spleen pulp, and also in the lymphatic glands, in which it persists longer than elsewhere, and from both of which it can be separated by cultivation. Bruce found it in the spleen in ten fatal cases. His results have been confirmed by Hughes, Gipps, Wright, Durham, Bassett-Smith, and many others. Injections of pure cultures give rise to a similar disease in monkeys and other animals, from whose blood the micrococcus can be recovered, cultivated afresh, and, on injection into other animals, again give rise to the disease. In five recorded instances inoculation— intentional and accidental— of cultures of the micrococcus into man has been followed by the characteristic symptoms of undulant fever after an incubation period of from five to fifteen days.
The Micrococcus melitensis measures 0.33 μ in diameter. It occurs generally singly, often in pairs, sometimes in fours, but never, unless in culture, in longer chains. According to Gordon it possesses one to four flagella. It is readily stained by a watery solution of gentian violet, and is best cultivated in a 1½-per-cent. very feebly alkaline peptonized agar beef jelly; in this medium, soon after inoculation, it appears as minute, clear, pearly specks. After thirty-six hours the cultures become a transparent amber; later they are opaque. No liquefaction occurs.
At one time believed to be a delicate organism, recent investigations have shown that the micro​coccus can live for a long time in water, in dust, or on the clothes of patients, and that it is not killed by cold or desiccation. Moreover, it is now known that it is excreted in the urine, and that it occurs in great abundance in the milk and urine of apparently healthy goats (50 per cent.) and cows, and in the urine of apparently healthy men. It is also found in dogs (9 per cent.), sheep, and horses. These facts account in part for the great frequency and dissemination of the disease in such insanitary places as Malta, to which place they specially refer.
Influence of age and residence.— The most susceptible age is between the sixth and the thirtieth year. Length of residence does not influence susceptibility. In Malta the natives suffer as well as visitors.
Influence of season.— In Malta and other places where the disease is endemic this fever occasionally assumes an epidemic character. The period of its greatest prevalence in Malta is the season of lowest rainfall, embracing June, July, August, and September; differing in this respect from typhoid, which, in that island, is more prevalent during the succeeding months. It is not confined absolutely to the summer months ; cases occur all the year round.
Local causes.— The disease tends to occur in particular towns or villages, in particular houses, barracks, hospitals, and rooms, and in particular ships, manifestly originating in limited foci of infection. The weight of evidence was regarded by some as pointing to its diffusion by air currents, and not by food or water. There is no absolute certainty on these points. Evidence is rapidly accumulating to show that milk is the most important medium.
Formerly it was supposed that in Malta this fever was linked to the immediate neighbourhood of the seashore, and that the sewage-laden, tideless condition of the harbour at Valetta was somehow responsible for its prevalence there. Zammit has shown, however, that the disease occurs all over the island, and that in some instances it is more prevalent in certain inland and relatively sanitary villages than ​in more insanitary towns and villages on the coast. Certain ships are notoriously foci of the disease, and, I believe, can carry the infection. Some time ago I saw a medical man suffering from a chronic fever, whose blood, in expert hands, gave the characteristic reaction, and who, if he had undulant fever, certainly got it from a ship which had recently been to the Mediterranean. He himself had never been in that part of the world, and had not been out of England for a year.
Influence of social conditions.— All classes are liable to this disease; the officer and his family as well as the soldier in barracks or the sailor on shipboard.
Mode of infection.— Although the possibility must not be ignored, undulant fever is not generally transmitted directly from one person to another; that is to say, is not usually directly communicable from the sick to the healthy. Seeing that the germ may abound and persist in vaginal mucus for a very long time, Lafont suggests that the infection may be acquired during coitus. The germ is readily conveyed by inoculation the prick of a contaminated needle will suffice. Zammit and others seek to incriminate the mosquito as an inoculator, and point, in support of their contention, to the special prevalence of the disease in the mosquito season, to the facts that of 896 mosquitoes examined bacteriologically it was found in 4, and that the disease has twice been conveyed to monkeys by infected insects.
A very striking circumstance is that in some hospitals the nurses and attendants in the fever wards are ten times more liable to contract the disease than people not so employed.
Possibly the infection is blown about by winds as dust, and being inhaled, or falling into the conjunctival sac, or on a wound or sore, obtains an entrance. Bearing in mind the presence of the germ in the excreta of man and animals, the dusty character of the soil of Malta and many Mediterranean towns, the extremely minute dose of a culture required for a successful inoculation, in any or all of these ways infection seems possible. I have seen a case, originating in England, in which a father was apparently ​infected by placing in his mouth the clinical thermometer used by his son recently invalided from Malta on account of the disease.
It is now known that the infection is conveyed in milk, and it has been suggested that it may be introduced in other kinds of food, or in water. Water as a usual medium may be dismissed, but there is strong evidence, judging from naval and military opinion, that, though the usual, milk is not the only medium. Facts point very distinctly to goat's milk as the most important medium of infection. The micrococcus is present in the milk of 10 per cent, of Maltese goats. Monkeys are easily infected by feeding them on such milk. Immediately on the goat's milk supply to the naval and military hospitals in Malta being stopped the cases of locally acquired undulant fever practically ceased. Formerly this fever was very common in Gibraltar. The milk supply of the garrison at that time was largely from goats imported from Malta. Gradually these goats have died out or been got rid of, and no more Maltese goats have been imported. Concurrently with this there has been a marked and proportional reduction of undulant fever cases in the garrison. In 1905 the s.s. Joshua Nicholson shipped 65 goats in Malta. An epidemic of undulant fever broke out on board, nearly all those who drank the milk of the goats being attacked.
IMMUNITY.— Bruce holds that one attack confers immunity from subsequent attacks; other authorities believe that one attack, so far from conferring immunity, actually predisposes to subsequent attacks. The latter is Bassett-Smith's opinion, based on the fact that he finds the bactericidal power of the serum and the phagocytic energy of the leucocytes lowered during, and for some considerable time after, an attack of the disease.
iNCUBATION period.— The period of incubation in the naturally acquired disease is difficult to fix.Cases have occurred as early as six days after arrival in Malta; others as late as fourteen and seventeen days after the subject of it has quitted Malta. Some have held that it may remain latent for months. ​Symptoms.— Undulant fever begins generally with lassitude and malaise, such as we associate with he incubation of many specific fevers, particularly typhoid. There are headache, boneache, anorexia, and so forth. At first the patient may go about his work as usual. Gradually the daily task becomes increasingly irksome, and he takes to bed. Headache may now become intense, and, in addition, the patient will suffer from thirst and constipation. At the commencement the symptoms, except that there is very rarely diarrhœa, resemble those of typhoid. There are no rose spots, however, then or at any subsequent period. There is evidence in the coated tongue, the congested pharynx, the anorexia, and the epigastric tenderness, of gastric catarrh; and the occasional cough and harsh, unsatisfactory breathing at the bases of the lungs indicate some degree of bronchitis or of pulmonary congestion. There may also be delirium at night. The fever is usually of a remittent type, the thermometer rising towards evening and falling during the night, the patient becoming bathed in a profuse perspiration towards morning. The spleen and the liver, but especially the former, are somewhat enlarged and, perhaps, tender. Lumbar pain may be urgent.
After a week or two of this type of fever, specially distinguished by pains and perspirations, the tongue begins to clean, and the appetite to revive; but, notwithstanding these signs of amendment, the patient still remains listless and liable to headache and constipation. He continues feverish and at times perspires profusely. Gradually, however, although the patient is anæmic and weak, subjective symptoms become less urgent; he sleeps well now, he has no delirium at night, and he can take his food, and this although the body temperature may still range slightly above the normal. Then once more, and perhaps over and over again, fever with all the former symptoms gradually returns; and now, if it has not declared itself before, the peculiar fleeting rheumatic-like affection of the joints or fasciæ, so characteristic of the dis​ease, shows itself in a large proportion of cases. One day a knee is hot, swollen, and tender; next day this joint may be well, but another joint is affected; and so this metastatic, rheumatic like condition may go on until nearly all the joints of the body have been involved one after the other. The patient may suffer also from neuralgia in different nerves intercostal, sciatic, and so on. Orchitis is an occasional complication. In some cases these complications are severe and characteristic; in others they may be mild, or absent altogether. In this respect the same infinite variety exists as in other specific fevers.
Perhaps the most characteristic feature of undulant fever is the peculiar behaviour of the temperature. In a mild case there may be a gradual ladder-like rise through a week or ten days to 103° or 104° F., and then, through another week or so, a gradual ladder-like fall to normal, the fever, which is of a continued or slightly remitting type, leaving for good without complication of any sort in about three weeks. Such mild cases are the exception. Usually, after a few days of apyrexia, absolute or relative, the fever wakes up again and runs a similar course, the relapse being in its turn followed by an interval of apyrexia, which is again followed by another relapse; and so 011 during several months. This is the "undulant" type from which Hughes derived the name he suggested for the disease -febris undulans.
In another class of cases a continued fever persists for one, two, or more months, with or without the usual rheumatic, sudoral, and other concomitants the " continued " type of Hughes.
Generally remittent or nearly continued in type, in a proportion of instances the fever exhibits distinct daily intermissions, the swinging temperature chart suggesting some septic invasion or a malarial fever. But there is no local evidence of suppuration to be found; neither, if we examine the blood, is the malaria parasite to be discovered; nor is the quotidian rise of temperature accompanied by any ague-like rigor, or at most only by a feeling ​of chilliness; nor is the disease amenable in any way to quinine. This is the "intermittent" type of Hughes. In other instances these types may be variously blended.
In some patients, not months merely, but years, may elapse before they are finally rid of the tendency to febrile attacks and characteristic pains and aches. According to Bassett-Smith, the average duration of the disease is four months. Many of our sailors and soldiers are permanently invalided from the services on account of prolonged or recurring attacks of undulant fever.
Sequelæ, complications, and mortality. —As a rule, by far the most serious consequences of undulant fever are the debility it entails, the emaciation, the profound anæmia, the rheumatic-like pains, the neuralgias, and such sequelæ as abscess, orchitis, mastitis, parotitis, boils, etc. It is prone to give rise to ovarian pains, dysmenorrhœa, amenorrhœa, menorrhagia, and to favour abortion and premature labour. The germ may pass into the fœtus, and children born under such circumstances are weakly.
Complications, such as splenic and hepatic enlargement, enlargement of the mesenteric glands, suppuration, phlebitis, chorea, various psychoses, arteritis, endocarditis, hæmaturia, etc., are met with occasionally during the long course of this disease. There is little risk to life; the mortality does not exceed 2.5 to 3 per cent. When death occurs it is usually from suddenly developed hyperpyrexia; occasionally it is brought about by exhaustion, by hæmorrhages and purpuric conditions, or by some pulmonary complication such as pneumonia. In a few instances the fever is of a fulminating type, rapidly ending in death from hyperpyrexia. Hughes, in his elaborate monograph, designates such cases " malignant."
Pathological anatomy and pathology.— This disease has almost no pathological anatomy. The spleen is the only viscus of which it can be said that it is distinctly diseased. In undulant fever this organ is enlarged (average 17 oz.), soft, and diffluent; on microscopical examination the lymphoid ​cells are found to be increased in number. There may be some congestion and even ulceration of the intestinal mucosa, but this is not an essential feature.
Diagnosis.— The diagnosis of undulant fever from typhoid is an important practical matter. It is exceedingly difficult in the early stages. Principal reliance has to be placed on the presence or absence of rose spots, of diarrhœa, of joint - complications, of sweats, the locality where and the season in which the disease was contracted, and, if available, the agglutination and precipitation tests.
According to Nicolle, there is a mononuclear increase, 70-80 per cent.; apart from this, microscopical blood examination, unless in a negative sense, is of no value in diagnosis.
Wright has shown that, both as regards sedimentation and agglutination, the germ of undulant fever reacts to the serum test in the same way as, and even more markedly than, Bacillus typhosus. A. weaker dilution (never less than 1 in 30 or 50) than in typhoid must be used. Dead cultures give the reaction, and can be conveniently kept in stock for diagnostic purposes; they are grown on agar, washed off with sterile normal saline, killed by heat at 60°C. or by formalin vapour. These observations have been abundantly confirmed. The agglutination reaction appears early in undulant fever as compared with typhoid, being available for diagnostic purposes by the end of the first week of the fever. It persists long after convalescence, often for years.
The unreliability of the serum test for undulant fever is in part explained by the researches of Nègre and Haynaud, who found that certain strains of M. melitensis agglutinated with normal sera, whereas other strains did not agglutinate with undoubted undulant-fever sera. The latter they name the " paramelitensis group." Bassett - Smith concurs in this. Therefore, before concluding from a negative reaction that any given case is not undulant fever, the serum should be tested with a paramelitensis culture.
After the fever has gone on for several weeks diagnosis is, of course, easier; in the early stages, on ​clinical grounds alone, and apart from the agglutination test, it may be almost impossible. It may be that it is only on the post-mortem table that we have the relative assurance, from the absence of ulceration in the ileum, that we have had to deal with a case of undulant fever. Cultures from spleen pulp, with subsequent inoculation into animals, should give reliable evidence if the results are positive. Tuberculosis, abscess, empyema, malaria, relapsing fever, and all the causes of continued high temperature of a septic type have to be carefully excluded in attempting a diagnosis. The possibility of the concurrence of another infection, typhoid for example, must not be overlooked.
Prognosis.— In the present state of our knowledge it is impossible to say how long any given case of this disease may last, what the risk to life may be, or what complications may be encountered. Birt and Lamb, from a series of valuable observations, conclude that important deductions may be derived from the behaviour of the agglutinating substances present in the blood. Their conclusions are, briefly, as follow: (1) Prognosis is unfavourable if the agglutinating reaction is persistently low; (2) also if the agglutinating reaction rapidly falls from a high figure to almost zero. (3) A persistently high and rising agglutinating reaction sustained into convalescence is favourable. (4) A long illness may be anticipated if the agglutination figure, at first high, decreases considerably. These conclusions are borne out by Bassett-Smith's very careful work.
Treatment.— Malta and those Mediterranean ports in which this fever is endemic should be avoided by pleasure- and health-seekers during the summer. Those who are obliged to live there all the year round would do well, at this season, to leave the towns and reside in places of healthy repute in the country. As a matter of precaution, in the endemic area the drinking-water, food, and drains ought at all seasons to receive special attention. All milk should be avoided, or sterilized by boiling, and food dishes should be washed with boiled water. Every care ​should be taken to avoid insect bites and other skin lesions. Laboratory workers must be careful in handling cultures of the micrococcus; the accidental introduction of the micrococcus into the conjunctival sac has sufficed to cause the disease.
When the diagnosis is sure, it is well to 'give a purge— none better than calomel and jalap— and to instruct the attendants to keep the patient's temperature systematically below 103° F. by cold sponging with vinegar and water or, if necessary, by cold bath or ice variously applied. In view of the prolonged nature of the fever, this measure is one of importance; at the same time, such treatment need not be applied too energetically, or so as to depress; a fall of 2° or 3° is all that is desirable.
Bassett-Smith recommends yeast and its products. Quinine and, on account of the joint affection, the salicylates are very generally prescribed. Both are useless, if not injurious. Phenacetin and similar antipyretics are also often given to bring down temperature; but the wisdom of employing depressing drugs in so chronic and asthenic a disease as undulant fever is, to say the least, questionable. Any threat of hyperpyrexia is best met as directed, namely, by early employment of sponging, the wet pack, or, if necessary, by the cold bath. Sleeplessness may demand hypnotics; headache, if severe, moderate doses of phenacetin, pyramidon, or similar drug; inflamed joints or testes, the usual local applications; constipation, enemata or aperients. In fact, the treatment of undulant fever resolves itself into a treatment of symptoms.
The therapeutic employment of vaccines of dead M. melitensis, prepared and administered according to Wright's methods, has been favourably reported on by Reid. In Bassett- Smith's hands the results have not been so favourable. After a prolonged and very careful trial, the latter concludes that if used during the acute phases of the fever, so far from doing good, they act detrimentally, but that in chronic cases, with slight relapses and low temperatures,— by stimulating slightly the machinery of ​resistance they are of real value, and it is to this type of case that he now restricts their use. Sergent concludes that the practical value of serum-therapy and vaccination in undulant fever has not been demonstrated.
The diet at first should consist of milk (in Malta, boiled); later, of broths and eggs and, if necessary, stimulants. Solids must not be freely given during high fever or when the tongue is coated. If appetite is present ordinary simple food may be taken. Lemonade or lime juice should be given after a time; not merely as a pleasant, thirst- relieving beverage, but with a view to averting scurvy not at all an improbable complication if the diet is too restricted over a long period. Feeding must be conducted with the greatest circumspection, avoiding overfeeding on the one hand and a low monotonous diet on the other. The tongue and the appetite are the best guides.
Exercise, travelling, and anything that tends to induce fatigue are prone to provoke relapse if indulged in prematurely; but a couch or chair in the garden is to be encouraged, weather permitting. The patient should rest for at least three weeks after temperature has become normal.
Flannel clothing should be worn, and frequently changed if there is much sweating.
Change of climate is not so necessary as in malarial affections, seeing that the disease may persist in England, and that it may gradually wear out in the endemic localities. It is not desirable to move a patient when fever runs high, or when debility is very great, or when the cool and healthy season in the Mediterranean is at hand. It must be considered that at this time winter is approaching in England, with climatic conditions very unsuitable for a patient who has become anaemic and debilitated from a long course of fever; at this season he would do much better in a milder climate. When, however, the case occurs early in the summer, or runs over the winter, then, in order to avoid the heat of the Mediterranean, change to England, if feasible and if it can be comfortably effected, should be advised, ​When possible the subject of undulant fever would do well to avoid the endemic area for one or more years after recovery.
Prevention.— Though mules, asses, oxen, cows, rabbits, and fowls can convey the micrococcus, there is no longer any doubt that goat's milk is the principal medium through which undulant fever is communicated to man.* This discovery has led to very striking and important results.
On the recommendation of the Mediterranean Fever Commission, the use of the milk of the Maltese goat was interdicted in the naval and military forces of that island. Immediately the incidence of undulant fever began to drop in the Navy from an average of 240 per annum up to 1906, to 3 in 1910, and in the Army from a previous average of 315 per annum to 9 in 1907. In 1909 the health authorities in Malta were authorized to kill all goats whose blood or milk gave the M. melitensis reaction. The goat population of the island was consequently reduced from 17,110 in 1907, to 7,619 in 1910. Concurrently the fever incidence in the civil population fell from an annual average of 632 to 318 (Eyre).
These facts suffice to indicate the direction preventive measures should take. It must be borne in mind that certain products of milk cheese, butter, etc. may communicate the germ, and, further, that infected goats may appear to be in perfect health and may milk satisfactorily.†
* ↑ * Experience has taught me to place little reliance on the serum-reaction test as ordinarily applied. Although with fresh blood and reliable cultures the reaction may be trustworthy, with stale blood and questionable cultures this test is most untrustworthy. Time after time, in London, I have got contradictory laboratory reports on blood from the same patients, presumed to have Malta fever. If the cultures in the London laboratories be so manifestly unreliable, it is probable that many of those in use in India and America are equally so, and that inferences as regards the geographical distribution of this disease, founded on the behaviour of these cultures with blood serum, are most un-
* ↑ * Proportion of infected goats in— per cent. Malta 50 Algeria 3.4 Tunis 30.7 Marseilles 34.2 According to Zammit, samples of infected milk are now being detected by the health authorities at Malta by employing the diluted milk for agglutinating cultures of M. melitensis macroscopically in capillary tubes; the result being subsequently confinned by a positive reaction of the serum of the suspected goat, which is then destroyed. This method is said to give rapid and reliable results, in addition to being more convenient than the agglutination reaction with serum alone.
* ↑ † It would seem that in South Africa infected goats often have marked arthritic symptoms, may suffer from mammitis, and are prone to abort.