Chapter XVI: Malta Fever

DEFINITION AND SYNONYMS

=Definition.=—Malta fever is a septicaemic condition due to the presence of the specific organism, _Micrococcus melitensis_, in the blood and various organs, especially spleen. It runs a protracted course, averaging three or four months, but is attended with very slight mortality (2%). Rare cases may run an acute course and show a high death rate. The fever course resembles that of a typhoid fever with two or more relapses, in that a step-like rise of fever for ten or twelve days is followed by a similar fall during the succeeding week or ten days, an afebrile interval of a few days then ensuing, to be followed by a second or third or even tenth febrile wave with the separating days of apyrexia. The course of the disease may last for a year or more attended with progressive anaemia and manifestations of neurasthenia. Very characteristic are sudden swellings of various joints which subside in a few hours to entirely disappear in a few days. Neuralgic manifestations, especially sciatica, are prominent features of the disease. It is chiefly spread by the milk of infected goats and can best be prevented by boiling such milk.

=Synonyms.=—Febris undulans (from the wave-like monthly accessions of fever). Mediterranean, Gibraltar or “Rock,” Neapolitan, Cyprus fever (from the geographical distribution). Febris sudoralis (from the night sweats). Mediterranean phthisis (from the bronchitis, anaemia and night sweats resembling phthisis). Melitensis septicaemia. Febris melitensis.

HISTORY AND GEOGRAPHICAL DISTRIBUTION

=History.=—It is generally considered that a disease described by Hippocrates, in which there was an irregular febrile course without crisis but showing relapses and running a very prolonged course, was probably Malta fever.

In 1861 Marston showed on clinical and pathological grounds that
the disease was different from typhoid fever.

In 1887, Colonel Bruce isolated the causative organism from the
spleen at autopsy and established the demands of Koch’s postulates
by reproducing the disease in monkeys with cultures from the spleen
and then recovering the organism from the monkeys.

Our present accurate knowledge of the epidemiology of Malta fever
and its connection with the use of the milk of goats is due to the
work of a Commission appointed to investigate the disease—1904 to
1907.

=Geographical Distribution.=—It is usual to consider Malta as the
focus of the disease, with the cities of the Mediterranean shores
showing quite a degree of infection. It is probable that the spread
of the disease has been in part connected with the importation
of Maltese goats, these animals being desirable on account of
their superior yield of milk. It is now known that outside of the
Mediterranean basin the disease exists in India, East and South
Africa as well as Northern Africa, China, North and South America
and the West Indies.

Mohler has shown that the disease under the names of “slow fever”
and “mountain fever” has existed in Texas and New Mexico for at
least twenty-five years.

ETIOLOGY AND EPIDEMIOLOGY

=Etiology.=—The causative organism, _Micrococcus melitensis_, is a small coccus, rather oval than round and about 0.4 micron in diameter. In morphology it is quite variable and may occur in pairs or in short chains and is Gram-negative. It emulsifies evenly and rapidly in a hanging-drop preparation and is nonmotile. Possibly on account of its showing a rather active Brownian motion there has been a reporting of slight motility by some authorities. Very striking is the characteristic of very slow growth so that cultures on agar fail to show colonies before the fourth day.

These minute transparent colonies become somewhat opaque and about
1/10 inch in diameter by the tenth day. Gelatine is not liquefied
and litmus milk is not altered. The optimum reaction of media
is about +0.75 to phenolphthalein and it grows best at the body
temperature. It has great powers of resistance to drying so that it
survives in dust for long periods.

Horses, cows, asses, as well as goats, are susceptible. It is very
difficult to infect rabbits, mice and guinea pigs. Monkeys have
been chiefly utilized in experimental work.

It would appear as if there were other organisms closely related
to _M. melitensis_ and a great deal is now being written as to
confusing serum reactions from the use of _M. paramelitensis_.

Evans and others have studied the relationship between _Bacillus
abortus_ and _M. melitensis_. Morphologically and culturally these
organisms are quite similar and Evans has demonstrated a marked
degree of cross-agglutination. This is a probable explanation of
the finding by Kennedy of agglutinating power in the sera and milk
of certain cows, but inability to isolate _M. melitensis_ from the
agglutinating milk.

=Epidemiology.=—Many experiments have failed to show any mosquito,
biting fly or louse as a probable factor in the transmission of
the disease. The infection is readily transmitted by subcutaneous
inoculation so that in a case in goat or man, with the cocci in the
peripheral circulation, it is reasonable to suppose that a biting
insect might transfer the infection by going directly from one
animal to another. There have been several laboratory infections,
but when we consider that of the great number of cases treated at
Haslar hospital and elsewhere in England, with frequent elimination
of the organism in the urine, and practically no infections among
the friends or attendants, it would seem as if usual methods of
infection were inoperative. There does not seem to be a carrier
problem in this disease. Urine showing bacterial contamination,
when dried and mixed with dust, has caused infection and
contaminated urine applied to the glans penis of a monkey caused
the disease.

As a large proportion of the prostitutes of Malta showed infection
and as _M. melitensis_ was found in urine and vaginal discharges
of many of these it is possible that sexual intercourse may be a
factor in transmission.

The Commission noted many cases of Malta fever among the goatherds. By agglutination tests it was found that one-half of the goats showed agglutinins in their serum. Of 28 monkeys given infected milk 26 became infected. Very conclusive was the case of the “Joshua Nicholson,” which ship carried 65 Maltese goats from Malta to the United States. Of ten of the crew who drank goats’ milk on the voyage, eight became infected. Two who boiled the milk escaped infection. It is reported, that when the goats reached the United States and were quarantined, a woman drank of their milk and became infected.

What may be deemed proof positive is the practical disappearance of the disease among the naval and military forces of Malta, as the result of boiling the milk, while still continuing among native civilians. Bassett-Smith has noted that in 1905 there were 798 cases among civilians and 245 naval cases. In 1907 there were 457 cases among civilians and only 12 cases in the naval forces.

There are however occasional cases which Shaw has considered as due
to carriers. As the organisms are excreted in faeces as well as in
urine, and as the course of the disease is so protracted, as well
as the convalescence, it would seem that the carrier factor should
be of more importance than facts would justify.

Mohler has noted that in Texas, where the disease has existed for twenty-five years, the Mexican goatherds boiled their milk and hence were rarely infected.

Gentry and Ferenbaugh, in Texas, noted that cases of Malta fever were most common in the spring and early summer months when the goats were in full milk and the ranchmen were caring for the kids and teaching them to suckle. The disease in certain areas was called “goat fever” and in others “dust fever,” this latter name coming from the idea that the dust-filled goat pens had to do with the disease.

The souring of milk does not destroy the germs of the disease,
hence transmission may be brought about by butter and cheese.

Malta fever was stamped out of Port Said by destroying all infected
goats.

Infection may occur: (1) By the stomach atrium (usual); (2) contaminated dust reaching lungs; (3) by subcutaneous injection.

PATHOLOGY AND MORBID ANATOMY

The germs are found early in the blood and spleen; and are also present in lymphatic glands and kidneys.

The blood is most apt to contain them at the height of the fever curve and a striking feature is the appearance in waves of the organisms in blood, urine or milk. While serum immunity reactions are striking features, there is some question as to the conference of immunity by an attack.

At postmortem we have an enlarged, congested, soft spleen with
swollen Malpighian bodies. The kidneys may show a nephritis and
the mesenteric glands be swollen. The intestines fail to show the
characteristic lesions of typhoid fever.

There may be evidences of myocarditis.

SYMPTOMATOLOGY

_A Typical Case._—Following a period of incubation, varying from ten to fifteen days, headache, malaise and anorexia set in with a step-like rise of fever from day to day.

The tongue is not heavily coated and is red at the tip and sides.

Constipation is the rule and there is an early tenderness and enlargement of the spleen. There is much to suggest typhoid fever in the gradual ascent of the remittent fever for about ten or twelve days and the gradual descent during the succeeding ten or twelve days, but the lack of apathy and slighter evidences of toxaemia differentiate. The patient is dejected rather than apathetic.

There is often a slight bronchitis, with cough, which, when
associated with a profuse sweating at night, may suggest phthisis.

Following the initial period of fever there is usually a short afebrile interval of a few days to be succeeded by a second, third or many of these febrile waves, thereby making one of the names, undulant fever, appropriate. Anaemia becomes marked and cardiac weakness, as shown by palpitation and rapid, irregular pulse, apparent.

The symptoms which aid us most in diagnosis are joint
manifestations and neuralgic pains. These may come on quite early
in the course of the disease or be delayed until succeeding febrile
waves set in. Swelling and pain, but without redness, of a single
joint may come on rather suddenly, to have the acute symptoms
subside in a few hours and to be entirely normal in three or four
days.

Pains in the sacro-iliac region or pains resembling those of hypertrophic arthritis of the spine may be noted.

It is however the peripheral nerves, even more than the joints,
for which the toxic effects of _M. melitensis_ show a preference.
The sciatic nerve seems to be most often involved and sciatica may
set in suddenly and acutely, to pass off in two or three days,
leaving a soreness over the course of the nerve and a tendency to
recurrence. Orchitis may occasionally set in. There is usually
albuminuria.

Insomnia is usually quite a prominent feature of the disease and
there is a great tendency for nervous prostration to develop.

The usual course of the disease runs for three or four months but may last almost a year.

=Other Clinical Types.=—(1) _The Malignant Form._—In such cases
instead of the insidious onset we have the characteristics of a
severe acute infection with high temperature from the beginning,
ranging from 103° to 105°F. Such cases may show vomiting and
early diarrhoea. This is followed by a typhoid state with cardiac
manifestations in the way of irregularity of the pulse. An ordinary
type of case may assume this malignant form and such cases may
develop a broncho-pneumonia.

(2) _The Intermittent Form of Hughes._—Here we have a type of case
similar to the typical one but less severe. It is a subacute form
which from time to time shows an intermitting fever. These cases
may fail to show evidence of serious illness and the patient may
continue his work although noting a progressive deterioration of
health. Some very mild cases which only rarely show slight fever of
a few days’ duration have been reported as _ambulatory_ cases.

(3) _The Disease in Infants._—Di Cristina and Maggiore have
described various forms of the disease as observed in infants in
Palermo. They note a hyperpyrexial type and an undulant type. A
type with anaemia and marked cachexia is very severe. Another form
shows cyanosis, irregular pulse and irregular respiration with
marked sweats. Again the symptoms may be those of a cerebro-spinal
meningitis.

=Sequelae and Complications.=—It should be borne in mind that
while not serious from a standpoint of mortality this disease is
to be dreaded by reason of the possibility of invalidism. The
neuralgic pains, insomnia and mental depression render patients
liable to the morphine habit. In pregnant women there is a tendency
to abortion. In rare cases we may have intestinal haemorrhages with
asthenic manifestations. Bassett-Smith has reported a case with
extensive purpura. The same author in paramelitensis cases has
noted the susceptibility to secondary streptococcal infections.

SYMPTOMS IN DETAIL

_Temperature Chart._—Except in the malignant form of the disease,
when the temperature may be rather continuous, the fever course is
a step-like ascent with daily remissions for about ten days and
then a similar descent. Following an evening rise of temperature
night sweats may be noted.

It is the wave-like succession of such courses of fever, separated
by afebrile intervals, that suggests the name undulant fever.

_Circulatory System._—The disease shows rather a toxic effect on
the heart as shown by palpitation and irregularity and rapidity of
pulse rate.

In the beginning of the fever, however, the pulse rate is not very
fast. Anaemia is a rather marked feature.

_Respiratory System._—A slight bronchitis with cough tends to
suggest phthisis in those cases which show rather marked night
sweats.

_Nervous System._—The organism seems to have a selective action
on the nervous system as shown by headache, various neuralgias,
insomnia, apathy and neurasthenia. Sciatica is probably the most
common peripheral nerve involvement.

_Joint Symptoms._—Very characteristic are the sudden and painful
swellings of various joints, especially hip, shoulder, ankle and
knee. Not rarely the costo-sternal articulations may be involved.
The acute symptoms subside in a few hours and the joints become
normal in a few days.

_Alimentary Tract Symptoms._—The tongue may have a slight furring
but the edges and tip are quite clean and red. Although anorexia
exists with the fever the appetite tends to return with apyrexia.
Constipation is usual. There is frequently tenderness of the
epigastric region.

_Genito-urinary System._—Other than for albuminuria and the
presence at intervals of the causative bacteria in the urine, there
is nothing of note, except the occurrence of orchitis in about 3
per cent. of cases.

_The Blood._—The white count is about normal or slightly
reduced—6500 on the average. The cells of lymphocyte type tend to
show an increase in percentage with a corresponding reduction of
polymorphonuclears.

There is a secondary anaemia.

The spleen shows early enlargement and tenderness.

DIAGNOSIS

=Clinical Diagnosis.=—The diseases most apt to be confused with Malta fever are typhoid fever, malignant tertian malaria, liver abscess, influenza, phthisis and kala-azar.

Besides the agglutination, complement fixation or blood culture
aids, we rely upon the sudden onset of joint involvement or
neuralgic manifestations as indicating Malta fever.

Usually the splenic enlargement about corresponds with that of
typhoid fever but at times it may be so marked as to equal that of
malaria or even kala-azar.

The presence of rose spots as well as the marked apathetic state
and the tendency to diarrhoea should aid in differentiating
typhoid. Unfortunately for diagnosis the leucopenia and polynuclear
percentage reduction is similar in the two diseases.

In kala-azar the double temperature rise in 24 hours with the _Leishmania_ bodies in spleen puncture material, instead of _M. melitensis_, are differentiating.

The short course and more sudden onset of influenza and the more
marked pulmonary symptoms of phthisis should prove diagnostic aids.

Liver abscess and empyema with their tendency to anaemia and sweating may prove confusing, but the history, leucocytosis and location of pain should differentiate. Then too the joint and nerve manifestations of Malta fever are absent.

=Laboratory Diagnosis.=—Eyre obtained cultures from blood from the 2d to 300th day of the disease. He recommended the taking of at least 5 cc. from a vein and that this be done at a time when the fever is at its maximum point—the days when the fever is at its maximum and in the evening of that day. By taking 20 to 30 cc. in an equal amount of citrated salt solution, as described in chapter on blood examination, one should have as great success as had Eyre—158 positives in 235 cases or 65.4 per cent.

It must be remembered that the colonies only appear about the
fourth day, becoming quite distinct by the tenth day.

Bassett-Smith takes about 10 cc. of blood in the afternoon during
pyrexial waves and distributes this blood in several tubes of
broth. He makes plates from these tubes every day. He also
recommends the taking of 1 cc. of blood which he allows to clot and
subsequently removes the serum and adds bouillon (clot culture).

Agglutination is the chief reliance in diagnosis. As result of two infections in his laboratory Widal uses emulsions killed by ¾% of formalin. He uses the microscopic method in the test with dilutions not exceeding 1 to 200. Such emulsions keep for at least a year.

In connection with agglutination tests Nicolle recommends that the
serum be separated at once and removed from the clot and Nègre
has shown that by heating the serum to 56°C., for thirty minutes,
reactions are not obtained with nonspecific sera.

Some workers prefer the macroscopic agglutination.

Complement fixation methods are of value but the application of
such tests is confined to large laboratories.

PROGNOSIS

The mortality is usually reported as 2% but there have been epidemics where the mortality, owing to the frequency of the very fatal malignant type, has exceeded 10%. It must be remembered however that the invaliding connected with the long course of the disease and protracted convalescence makes Malta fever a serious affection. Neurasthenia, susceptibility to neuralgias, cardiac weakness and formation of morphine habit may result from the disease.

PROPHYLAXIS AND TREATMENT

=Prophylaxis.=—The danger from carriers seems slight but should be considered.

Disinfection of excreta, in particular urine, is important.

Boiling of goat’s milk or killing of infected goats is a prime consideration.

A rapid method of detecting infected goats is by carrying out a
macroscopic agglutination of _M. melitensis_ with the milk obtained
from goats. The lacto-reaction should be confirmed by a serum one.

=Treatment.=—There is no specific treatment generally recognized as efficient. Recently, an anti-melitensis serum, from animals injected with the nucleo-proteid material from the organisms, has been used with some success.

A serum prepared by injecting horses intravenously with the
specific organism has been recommended by Sergent in doses of 50 cc.

Bassett-Smith recommends an autogenous vaccine, during the afebrile
period, in doses of from 50 to 200 millions. He thinks that the
best results are obtained with sensitized vaccines. During acute
phases the vaccine treatment is detrimental—it is only in chronic
cases that such treatment is of value. Some prefer to give doses of
10 million or so at short intervals. He also thinks yeast in 2-dram
doses to be of value. Phenacetin or aspirin may be given, but the
heart weakness makes extensive use of these analgesics dangerous.

The diet should be that for any acute disease but the protracted
course makes it necessary to have regard to an adequate food value.
Care should be taken to avoid chilling or fatigue.

Some recommend moderate use of alcoholic stimulation but this
treatment is questionable.

Cold sponging and local applications to joint or nerve involvements
are indicated.

Morphine should be employed with great caution.