Annual Incidence

The accompanying graph (1) shows the annual incidence over three and a half years among all troops in the Middle East, and it will be seen that the epidemics recurred each year at the same time but with less intensity, and were associated with, but later than, the fly maximum. Graph 2 shows 2 NZEF incidence from 1942 to 1944. Among New Zealand troops there is not the same falling-off in incidence, due no doubt to such factors as large numbers of reinforcements.

The Middle East is considered an endemic area where jaundice is a common complaint of children but rare in adults, whereas adults coming into the area are readily infected.

Sub-clinical Attacks

All figures of case incidence are to some extent inaccurate because of the large numbers who had sub-clinical attacks, as will be described later. These being of all grades of severity, many could page 502 not be located as they did not report sick. However, it is clear that among New Zealand troops the incidence must have been much higher than is indicated by figures.

page 503

Some Inferences

Studies by Van Rooyen and Kirk (1945) conclude that the virus is distributed widely throughout the Mediterranean and that the local adult population is immune to attack due to resistance acquired in childhood, either from the disease or by consuming food contaminated by the virus. Thus, in troops occupying an infected locality, the mechanism of their response to infection resembles that of the local children. By patronising cafés and eating-houses, every man would soon ingest infected material. Some acquired the disease and some eventually an immunity. However, in the case of the epidemic at Alamein, the doses of virus were probably so intense that many with moderate degrees of resistance would be infected. This may account for the mildness of many cases.

Susceptibility of Officers

Spooner (1943) noted that British officers were 4.7 times as prone to infection as other ranks. This did not apply to the same extent among New Zealand officers, but the incidence was higher than among the men. This is explained by the fact that an officer lives a more protected life than the soldier and enjoys better conditions all round in base camps, the contrast being greater in the British Army, where the susceptibility in an epidemic was higher and the incidence higher. The contrast did exist in the 2 NZEF in base units, but to a lesser extent. Officers in the field, of course, ran the same risk of infection as the men, and the incidence depended on the resistance gained during residence in the country while in base camps, etc.

British troops showed the greatest susceptibility to hepatitis of all troops in the Middle East, while New Zealand troops came next, whereas Indians and Maoris showed the least susceptibility. This latter statement is so far unexplained, but was a very noticeable feature.

Prevention of Hepatitis

Studies of the virus show that it is extremely resistant. It has comparable qualities to the virus of serum jaundice (Havens, 1945), which will traverse bacteriological filters of the Seitz and Berkefeld types, it withstands equal volumes of phenol and ether of a 5 per cent concentration for many months, and resists heating at 50 degrees C. for an hour or freezing or drying for several weeks (Memorandum, 1943).

As little as 0.1 c.c. of serum or the prick of an infected needle has been known to convey the infection (Bradley, Loutit and Maunsell, 1944; Salamen, King, Williams and Nicol, 1944).

page 504

The hygiene of the 2 NZEF units was excellent, judged by the dysentery and jaundice rate, and if one considered the base camps. Here one can say that hepatitis was controlled. However, in the desert camp areas, in spite of the best that could be done under the conditions, the control failed.

The efforts of sanitation, however, were magnificent under trying conditions (Richmond and Gear, 1945). They could conceivably be improved by attention to all aspects of sanitation and cleanliness, but it is just as well to remember that the highest incidence in the Eighth Army in the desert was 8 per 1000, and it would require many more men than that to advance sanitation closer to perfection than was obtained.

McKinlay and Truelove (1947), in carrying out investigations among New Zealand troops in Italy, made important contributions to the knowledge of this disease. They found that among the men who had experienced previous epidemics the initial incidence of infection was highest and gradually decreased, whereas among men recently arrived in the Middle East and Italy the initial incidence began low and rapidly increased.

They also noted the low incidence among Maoris, and commented on the fact, also, that a group which had not previously passed through an epidemic was three times more susceptible than old hands.

Comparison with Poliomyelitis

Modern work has shown that poliomyelitis virus is more easily recovered from stools than from naso-pharyngeal secretions (Trask et al., 1938, 1940, 1943; Kramer et al., 1939; Sabin and Ward, 1941; Paul, Havens and Van Rooyen, 1944).

Before it is possible to appreciate the underlying nature of these two virus diseases one should abandon older ideas which persistently endeavour to explain their epidemiology by case to case contact, oblivious of the existence of powerful immunity effects.

Both infective hepatitis and poliomyelitis are primarily intestinal maladies. The susceptible individual who ingests infective hepatitis virus develops the secondary complication of jaundice more frequently than do those who develop secondary paralytic phenomena after ingestion of poliomyelitis virus.

There have been in the past many adherents to the theory that the spread of infective hepatitis is of a catarrhal nature. One can only say that there is no evidence to support it out of the studies and experience in 2 NZEF, and that the aetiology and means of spread under wartime conditions in Egypt and Italy are clear.

page 505

The Pacific

The only figures available are for the latter half of 1943 and the first half of 1944. These, however, are too small to draw any conclusions from, as the last six months of 1943 produced 45 cases and the first six months of 1944 40 cases. However, the maximum incidence occurred in November and December, and again this suggests the heat of summer and the role played by flies in the spread.

Hospitalisation

At first it was thought that some attempts at isolation of cases should be made, but this appeared so impracticable under conditions in Egypt that it was waived and no efforts in this direction were made. It was found convenient to have these cases together, however, for ease of nursing, and this allowed the charge of a ward to be left to a junior member of the staff. Although some cases did not report sick, it became apparent that if men remained in the line the disease was more severe eventually and more protracted, and that the tendency to relapse was greater. Field units were encouraged to evacuate patients as sitting cases to base hospitals so that a full spell in hospital and adequate convalescence could be arranged. It was soon found to be a false economy to discharge men early or to hurry their return to the front line, because of the dangers of relapse, as well as the risk of continued poor health. Only those units who could give a full, unhurried convalescence were encouraged to keep their cases. The policy of having as many as possible of the New Zealand troops evacuated to New Zealand hospitals allowed a better study of the disease, and also allowed more satisfactory treatment as many other hospitals were inclined to discharge patients still jaundiced, because of lack of space, and among these one saw the highest relapse rate.

During the Alamein epidemic 1 NZ General Hospital and 2 NZ General Hospital handled most of the cases, and fresh demands were met by more tents being put up. Even though 1 NZ General Hospital enlarged from 900 to 1300 beds in a few weeks, most of the cases were accommodated in 80-bed tents, and were required to stay in bed except for going to the lavatory and ablutions.

In many cases conditions were not ideal and control was difficult, but the results were satisfactory and the criteria for discharge was disappearance of the jaundice and a clear urine and a few days of getting up gradually.

The routine (after the urine was clear) was 1 hour up first day, 2 hours up second day, 4 hours third day, 6 hours fourth day, and then off to a convalescent camp, where individual progress was page 506 watched and each case judged on its merits. In many cases livers were still enlarged on discharge, and it is a matter for conjecture whether these cases should not have been held longer.

Medical Officers

It was found that any one MO was able easily to look after 100 to 150 cases of infective hepatitis as well as do other routine duties. This included clinical examinations, writing of notes, and all the appropriate paper work and urine examination.

Immunity

It was noted that no particular physical type of soldier was more liable to become infected, but that the chances decreased with age. Infection in most cases conferred an immunity, but some very slightly infected had infections a second time. The average full infection usually conferred an immunity, but some men failed to develop an immunity at all and had repeated reinfections. Maoris had a strong immunity, which seemed to be a racial characteristic as the chance of infection was greatest in those who had a marked admixture of white blood.

Clinical

Non-icteric Cases: These cases at first seemed somewhat of a mystery and were inclined to be classed with the dyspepsias. They represented the purest form of infection with the virus and the gastro-intestinal infection, and yet it is hard to account for the fact that many had enlarged livers with no jaundice. It is best to consider cases of all grades beginning with (a) those where the infection was essentially gastro-intestinal in type and of short duration, (b) those in which the gastro-intestinal infection was associated with an enlarged liver and no jaundice, (c) those in which the gastro-intestinal infection was negligible clinically and the enlarged liver was found to account for some degree of ill-health but still no jaundice, and then (d) those with gastro-intestinal symptoms and jaundice of varying degrees.

It is impossible to say how many of the non-icteric cases occurred as these rarely came to hospital; but it is considered that there were very many of them. Eventually we came to the conclusion that a lot of persistent dyspepsia was probably originally due to the infection with the virus, and also one saw many who had gastrointestinal infections of four to five days' duration only, who had all the characteristics of virus infection.

page 507

Clinical Review of 1942 Epidemic

At the onset of epidemics the cases were milder than those seen in previous years and had fewer complications, but as time went on they became more severe, the icterus lasted longer, debility was greater, and relapses more frequent. As the greatest number were mild they form the basis of this description, but there were, during the later stages, all types, as will be seen in the text. Although it is recognised that icterus is only one symptom of this disease, it is convenient to divide it into two stages, the pre-icteric and the icteric.

Pre-icteric Stage: In all epidemics in the 2 NZEF this was the period of greatest malaise and discomfort, and was the one most often spent outside hospital. Many examples, however, were able to be studied in the wards, and the briefest statement to cover this stage would be that it was usually pyrexial illness associated with acute gastritis. That acute gastritis is present was proved at post-mortem in one case, and in another, when an ulcer in a Meckels diverticulum perforating the mucous membrane showed the typical changes on the third day of the pre-icteric stage.

The onset was usually sudden with a close resemblance to sandfly fever, presenting a mild shivering attack, temperature 102–103, headache, generalised aches and pains, backache, and considerable mental depression. Some cases were apyrexial or had a mild fever only. Two presented as initial symptoms a generalised urticaria which cleared and recurred during the first three days of the illness. The icteric tinge of the skin was readily seen in urticarial wheels. Whatever opened the train of symptoms, be it fever or just malaise, within twenty-four hours the classical features of this stage appeared, dyspepsia and anorexia, which were almost universally present and were the most striking and most complained of symptoms and the greatest cause of discomfort to the patient. No matter if fever were present or not, loss of appetite, nausea, lassitude, general malaise, and indigestion were always regarded with suspicion, and jaundice expected and waited for.

Anorexia was frequently complete and associated with nausea, occasional vomiting, and, in a few instances, persistent hiccough. Dyspepsia was persistent, severe, aggravated by food, and failed to respond to alkalies. Constipation was common and diarrhoea rare, the tongue was clean and moist. Fat intolerance was seen early, and any appetite that was present was capricious. This pre-icteric stage lasted five to seven days, but varied from none to twenty-one days. The dyspeptic symptoms usually became steadily more severe and the pyrexia followed no uniform pattern, but varied between a chart persistent at 101 or 102, one with a daily swing between normal page 508 and 102 and 103, a completely irregular picture, a low fever of 99 or 100, or one that settled to normal within two or three days and stayed there.

From the first or second day there was pain under the right costal margin, both at rest and on movement, tenderness on pressure in this region, and a liver edge palpable one inch below the rib edge. Although the liver was enlarged in practically all cases, it was the exception to feel a spleen, the fauces were normal, the breath not offensive and the facies unchanged, but the patients felt ill and miserable, were unable to concentrate, and difficult to satisfy.

General physical weakness was felt by many of those whose pyrexia and dyspepsia were not of sufficient severity to require evacuation to hospital, and that, combined with a loss of interest and inability to concentrate, eventually decided many to report sick.

Rashes: Two cases were seen who presented a rash typical of typhus fever during this stage, but because of the mildness of the illness and the presence of all other typical signs of hepatitis were accepted as such.

This pre-icteric stage, which proved a source of humiliation to many medical officers in the early days of the epidemic and soon became easily recognised, passed insensibly into the icteric stage.

Icteric Stage: The full development of jaundice normally occupied five to seven days, but was noticed to be as short as three days or, in the severe cases, to deepen steadily for as long as three weeks. At first the urine was noticed to be getting dark, and it was surprising how many of the milder cases continued at work until this stage. Two days later a tinge of yellow was visible in the conjunctival folds of the lower lid, which spread concentrically towards the pupil, and on the fifth day the conjunctiva was evenly and deeply stained, the urine mahogany in colour, and the skin evenly and faintly yellow. In the majority of cases this stage of icterus was obvious but not severe, and reached its full intensity in five to seven days or less. The length of the disease could normally be estimated from the depth of jaundice after one week. Some mild cases were already beginning to clear or had reached a stationary stage by the fifth day, whereas the more severe and prolonged cases were still deepening in colour. It followed in most cases that the degree of icterus reached by then indicated the rapidity with which it would clear and the extent of the resulting debility. A few exceptions to this occurred, in which cases a sudden increase in the severity indicated a more prolonged and severe illness.

The temperature if not already normal at the onset of the icterus became so very soon, settling by lysis, and only rarely did pyrexia remain without heralding the presence of some complication or intercurrent infection. The dyspepsia and anorexia commenced to page 509 improve once jaundice appeared, and in 90 per cent of cases was completely gone when the jaundice was fully developed. As the dyspepsia vanished the appetite became enormous, and in some cases most capricious, being only satisfied by large quantities of tomatoes, cucumbers, or oysters. A certain fat intolerance remained in some and lasted for several weeks.

In the mildest type of case (in this series over 50 per cent) jaundice began to fade very soon after it was fully developed, that is, from the fifth to the seventh day. The fading was normally rapid and was almost gone about the fourteenth day after its appearance, leaving only a mild staining of the conjunctiva. The fading took place, first from the skin, then from the conjunctiva and lastly from the urine, which usually showed a trace of bile on testing for several days after all else appeared normal.

In a considerable number, however, the jaundice remained stationary with daily fluctuations for about seven days and cleared in a further seven to ten days, whereas the most severe continued with deep icterus up to a period of six weeks or more before clearing. The longest case of icterus in this series was eight weeks.

During the stage of clearing all symptoms had usually gone except those of weakness and lassitude. The stools darkened early and the urine became paler early but was the last to clear completely, as determined by laboratory tests.

During the stage of fully developed icterus the liver could be felt one to one and a half inches below the costal margin. In cases of prolonged or deepening icterus it would enlarge still further up to 2.inches or even more, but once the jaundice began to fade in nearly all cases it returned to normal size with rapidity.

In the majority of cases in fourteen to twenty-one days after the onset of jaundice the patient would be quite clear again with a liver of normal size and would commence to get up. This was taken slowly and a week allowed to reach the stage of being up all day before going to a convalescent depot for a further two or three weeks.

In the more severe cases, which were rarely seen early in the epidemic, but formed a large proportion of those at the end, the pre-icteric stage presented no unusual features, but the onset of the icterus was not always accompanied by fall in temperature and return of appetite.

The jaundice gradually increased, or did so in a series of exacerbations, while the irregular fever persisted for seven to ten days and the dyspepsia diminished only gradually, and did not vanish. Malaise and lassitude became more evident and sleeplessness the rule, the skin became deeply yellow, and in those whose jaundice page 510 lasted four to eight weeks pruritis was severe, haemorrhages frequent, and loss of weight alarming.

No particular type of patient or one belonging to any particular age group was more affected in this way than any other, and in this series no deaths occurred in the later stages no matter what the extent or severity of the jaundice.

Persistent Pyrexia: Where this occurred and lasted one or two weeks during the icteric stage, in the absence of any recognisable complications it indicated a severe and prolonged illness. It was an infrequent complication.

Distended Abdomen: This was seen in several cases, and if associated with fever suggested an accompanying typhoid infection. Although a few cases did have this as a superadded infection, the majority of cases did not, and the disorder vanished without therapy.

Pruritis: This was a distressing accompaniment of some of those cases in which icterus was prolonged and deep. It became worse towards evening and at night, was generalised and difficult to relieve. One case only responded brilliantly to ephedrine gr.½, whereas others received temporary relief from luminal, and calamine and phenol lotion.

Haemorrhage: Cases severe enough to show pruritis often showed signs of a haemorrhagic tendency in areas subjected to scratching and other mild traumata. This was usually an indication of more severe haemorrhages to come from lips, gums, nose, stomach, bladder, and rectum, but prompt exhibition of vitamin K intramuscularly prevented any of these becoming of serious importance.

Recurrent Icterus: A recurrence of a fading icterus was not infrequent. In some cases it developed when the original icterus had almost faded. It only increased the time of the illness and the convalescence necessary. In many cases it seemed to be related to indiscretions such as getting out of bed without permission or unwarranted exercise in the earliest stages of getting up.

Relapses: These were of two types:

1.	With Icterus: Presenting a complete picture of the whole disease, usually much more severe and prolonged than the original illness. These relapses occurred three to four weeks after the complete subsidence of the original infection, and in a few cases second relapses also occurred.
2.	Without Icterus: These cases presented a picture of acute gastritis and were recognised by the patient as being identical with his original symptoms, were associated with a slight enlargement of the liver, and took three to four weeks to recover. page 511 There is no evidence that these relapses were related to the taking of alcohol. It is estimated that the relapse rate was 3 to 4 per cent.

Persistent Liver Enlargement: Mild cases of hepatitis usually had normal livers on discharge from hospital, but in the more severe and relapsed cases enlargement tended to persist and was associated with recurrent dyspepsia and malaise. Enlarged livers have been found three or four months after the recovery from icterus. These patients were far from well and required regrading. The future of these men is uncertain at present, but some, seen six years later, have normally sized livers and no symptoms.

Mental Symptoms: Examples of mild depression were often seen, but in prolonged icterus confusional states, which recovered completely during convalescence, were common.

Treatment

All cases were confined to bed except for a daily bath and visits to the lavatory, but even this was forbidden in any but the milder type of case. It was noticed that rest in bed had an appreciable effect on the rapidity of recovery.

Diet

Fat-free diet was given until the appetite returned. After that no restrictions were made. Glucose was given in the form of drinks or barley sugar in as large quantities as possible. Fluids were forced during the whole illness.

Medicine

Sod. Sulph. was given each morning. Alcohol was forbidden during the illness and for one month after

Severe Cases

These cases were a great anxiety because of the mental changes, tendency to bleed, and the difficulty in getting in sufficient fluids.

Intravenous fluids and glucose were given early in all severe cases.

The fluid intake was kept at 6 pints a day and 100 grammes of glucose or more was given.

Vitamin K was given to prevent haemorrhage; vitamin B to prevent peripheral neuritis.

Occasional blood transfusions were resorted to as necessary.

Amoebae

In Italy, during treatment of hepatitis, it was found that many cases had persistent diarrhoea. On investigation this was found to be due to amoebic infection, no doubt introduced by the fly as was the virus of infective hepatitis.

Pensions Aspect

An opinion expressed by Dr D. Macdonald Wilson of the War Pensions Department in 1952 was that infective hepatitis had not page 512 resulted in any pensions liability. In a few cases only were some vague dyspeptic symptoms associated with some slight enlargement of the liver ascribed to a previous attack of hepatitis.

Statistics

The importance of infective hepatitis in its effect on 2 NZEF in the Middle East and Italy is shown by the following statistics:

Admissions to medical units July 1941 to December 1945 were 7051. (These represented nearly 9 per cent of all admissions and the total was greater than that for any other disease, and the length of stay in hospital and convalescent depot was second only to pneumonia.)

Deaths from hepatitis were 6 out of a total of 190 for all diseases.

Cases evacuated to New Zealand numbered 124.

In 2 NZEF (IP) there were only 85 hepatitis cases in the total of 6248 admissions to medical units.

INFECTIVE HEPATITIS

Troops in Italy and Sicily 1944

Comparative Morbidity Rates

UK STANDARD = 100

page 513

Infective Hepatitis and Serum Jaundice

The relationship of infective hepatitis to serum jaundice, postarsenical, and post-yellow-fever-vaccine jaundice remains a mystery. No laboratory animal has been found susceptible to infection with any of these varieties of jaundice.

Bigger (1943) has demonstrated that jaundice following antisyphilitic treatment was due to faulty sterilisation of syringes and needles contaminated with homologous serum jaundice virus. Sheehan (1944) and Salaman et al. (1944) and others have provided confirmation.

Dible and McMichael (1943) studied the histopathology of liver biopsy tissue from cases of arseno-therapy jaundice, and concluded that the appearances of the organ were more compatible with damage by an agent similar to that causing serum jaundice or epidemic hepatitis.

The relationship of serum jaundice to infective hepatitis presents a conundrum, for if it were eventually proved that the two were identical then the existence of subclinical, silent, blood-borne infective hepatitis would claim fresh significance.

Some believe that they are aetiologically different because infective hepatitis is spread by contact and has an incubation period of twenty-eight to thirty days, whereas clinical serum jaundice is normally caused by parenteral administration of icterogenic serum, and has an incubation period of eighty to a hundred days according to Paul et al. (1945), Steiner (1944), and Beattie and Marshall (1944). The latter also discovered that it was possible to reduce the incubation period of serum jaundice to thirty days by feeding infective serum. Evidence in favour of their identity has been provided by Sheehan (1944), who noticed that infective hepatitis virus may be conveyed from one man to another by unsterile needles and syringes used for aspirating blood, and that the ensuing malady assumed the character of typical serum jaundice after an incubation period of three months. Efforts to isolate virus from the faeces of serum jaundice cases by McCallum (1945) and Neefe, Stokes, and Gellis (1945) have been unsuccessful, and it therefore seems that the intestinal tract contents are not infective in serum jaundice.

Conclusions of the opposite kind have been reported by Paul et al. (1945), who found that three patients who had recovered from serum jaundice six months earlier, later proved susceptible to experimentally induced infective hepatitis. The latter have epitomised the present position by stating that the outstanding difference between serum jaundice and infective hepatitis rested in the length of the incubation period. Neefe, Stokes, and Gellis page 514 (1945) have commented that ‘Normal persons are much more likely to develop the disease when the agent is administered orally than when it is injected parenterally’, a fact which we regard as one of fundamental importance in the establishment of infective hepatitis as a primary pathological affection of the gut.

The two diseases may be closely related in that serum jaundice represents the artificial production of infective hepatitis in a proportion of instances: it cannot yet be said that all serum jaundice belongs to this category. The question of the aetiology of post-arsenical serum jaundice and infective hepatitis bristles with unsolved academic problems and practical obstacles to progress, but the subject is of as much interest in peace as in war and justifies intensive research into the pathogenesis of these icterogenic virus agents.

Clinical Pathology

Blood Picture: In the pre-icteric stage there is leucopenia with an absolute neutropenia and an increase in the large lymphocytes. In the icteric stage the white cells increase again and there is a definite absolute monocytosis, and then a gradual return to normal in about six weeks.

Liver Function Tests: These were rarely carried out among New Zealand patients, and it was considered there was no single test which would differentiate between infective hepatitis, chronic hepatitis, cirrhosis, and obstructive jaundice. Higgins and his colleagues consider that the estimation of bilirubin, phosphatase, albumin, and globulin in the plasma from a given specimen provided as much information as could be got from liver function tests.

Pathology

The changes in hepatitis consist of hepatic cell necrosis and autolysis with a leucocytic and histiocytic reaction and infiltration. In severe cases there is disorganisation of the architecture of the hepatic lobules. The centres of the lobules show the cell necrosis and autolysis most markedly and the cellular infiltration is greatest round the portal tracts. The end stage may be acute or sub-acute necrosis or cirrhosis.

PERIPHERAL LOBULAR NECROSIS IN HEPATITIS

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