Rectal biopsy in patients presenting to an infectious disease unit with diarrhoeal disease.

The role of sigmoidoscopy and rectal biopsy was investigated in patients referred to an infectious diseases unit with diarrhoea. Seventy-four patients were studied. Nine patients (12%) had inflammatory bowel disease, either ulcerative colitis or Crohn's disease. Thirty-six patients (48%) had infective diarrhoea. A wide variety of conditions accounted for the diarrhoea in the remaining patients. Sigmoidoscopy was abnormal in 25 patients and rectal biopsy in 56. The abnormalities in rectal mucosal histology were classified into six grades. Some patients with infective diarrhoea showed rather characteristic histological changes which may be of diagnostic value. Eight showed features which suggested a diagnosis of inflammatory bowel disease. However, repeat rectal biopsy in the convalescent period showed a striking improvement in the patients with infective diarrhoea. In contrast, the histological changes persisted in the patients with inflammatory bowel disease. Repeat rectal biopsy may be essential before making a firm diagnosis of inflammatory bowel disease in some patients who present with diarrhoea and apparently typical histological changes.     

Co-existing Coeliac and Inflammatory Bowel Disease in a Patient with Turner's Syndrome

Summary: A patient, aged 20, with Turner's syndrome was found to have both coeliac disease and chronic ulcerative colitis. Although a gluten-free diet restored to normal the jejunal biopsy, persisting diarrhoea was found to be due to coexisting left-sided ulcerative colitis. A search of the literature revealed only three detailed reports of chronic inflammatory bowel disease in coeliac patients, one of coeliac disease in Turner's syndrome and three of inflammatory bowel disease in Turner's syndrome. Growth failure with coeliac or inflammatory bowel disease in females, may call for a chromosomal study, even in the absence of webbing of the neck. The reason for three uncommon disorders occurring in this patient remains obscure.     

Is there an association between coeliac disease and inflammatory bowel diseases? A study of relative prevalence in comparison with population controls

OBJECTIVE: The relationship between coeliac disease and inflammatory bowel disease (IBD) is controversial. The aim of this study was to determine the prevalence of coeliac disease in IBD and the prevalence of IBD in coeliac disease. MATERIAL AND METHODS: Patients were enrolled from specialist IBD and coeliac clinics. Antigliadins, endomysial, tissue transglutaminase antibody and total IgA levels were measured in IBD patients. Patients with positive antibodies were offered a duodenal biopsy. The notes on coeliac patients were reviewed for colonoscopic and biopsy findings. Controls were recruited from the local population. RESULTS: The study included 305 patients with coeliac disease, 354 with IBD and 601 healthy controls. The IBD group comprised 154 ulcerative colitis (UC) cases, 173 Crohn's disease, 18 indeterminate colitis and 9 cases of microscopic colitis. Forty-seven patients had positive antibodies and 3 had villous atrophy on biopsy. All three patients had positive anti-tissue transglutaminase antibodies but only two were endomysial antibody (EMA) positive. Ten coeliac patients had IBD (5 UC and 5 lymphocytic colitis). Five controls had coeliac disease and 2 had IBD (1 Crohn's disease and 1 UC). Stepwise multiple logistic regression showed only antibody positivity as being significant (p<0.0001). CONCLUSIONS: The prevalence of IBD in coeliac disease was increased 10-fold compared with that in controls (odds ratio 9.98, 95% CI 2.8-45.9, p=0.0006), while the prevalence of coeliac disease in IBD was comparable with that in controls (odds ratio 1.02, 95% CI, 0.24-4.29, p=1.0).     

Association of primary sclerosing cholangitis,ulcerative colitis and coeliac disease in female siblings

Primary sclerosing cholangitis is a rare, cholestatic liver disease, most commonly affecting young men. The association of primary sclerosing cholangitis with other autoimmune disorders, although rare, indicates a genetic predisposition for this disease. We describe, for the first time, the association of primary sclerosing cholangitis, ulcerative colitis and coeliac disease in two sisters. Ulcerative colitis was mild and preceded liver disease in both patients. There were no symptoms of coeliac disease, and its silent form was diagnosed on the basis of serological tests. Both patients carried HLA molecules DR3 and DQ2. Although HLA DR4 was not found, there was a rapid progression of liver disease to cirrhosis and cholangiocarcinoma in one patient. The familial occurrence of primary sclerosing cholangitis, ulcerative colitis and coeliac disease supports the hypothesis of genetic predisposition for these diseases.     

Clinical and laboratory indicators of extent of ulcerative colitis. Serum C-reactive protein helps the most

We estimated the extent of the inflammatory mucosal lesion by colonoscopy and biopsy in 60 patients with their first attack of ulcerative colitis. Proctitis was found in 12, proctosigmoiditis in 19, left-sided colitis in 10, and extensive colitis in 19. Fourteen clinical variables and laboratory measurements (bowel frequency, stool consistency, rectal bleeding, fecal mucus/pus, temperature, pulse rate, white blood cell count, hematocrit, sedimentation rate, serum iron, serum albumin, serum alpha 2-globulin, serum C-reactive protein, and seromucoids) were determined. All the variables except rectal bleeding and hematocrit were correlated (p less than 0.001) with the extent of colitis. On stepwise discriminant analysis, only C-reactive protein distinguished proctosigmoiditis from more improved the discrimination. Cross-validation by the "jack-knife method" showed that 86.7% of patients were correctly classified, the errors consisting in underestimation of disease in 8/29 patients with extensive colitis.     

Incidence and prevalence of ulcerative colitis in Punjab, North India

INTRODUCTION: Ulcerative colitis occurs worldwide. It is considered common in most of Europe and North America and uncommon in most of the developing Asian countries. The incidence/prevalence of ulcerative colitis varies not only according to geographical region but also with race and ethnicity. There are no reported data from India on the incidence of the disease and its prevalence. Material and methods: A house to house survey was conducted by questionnaire, formulated to enquire about symptoms that are suggestive of ulcerative colitis. Those with prolonged diarrhoea with or without rectal bleeding were considered as suspected cases. These suspected cases were subjected to video sigmoidoscopy/colonoscopy and rectal biopsy. In addition, patients already diagnosed and receiving treatment for ulcerative colitis, encountered during the survey, were reviewed. Resurvey of the same areas was conducted after a one year interval to detect new cases. Using direct methods, standardised rates were calculated using world standard population weights 22, 18, 16, 12, 12, 9, 7, 3, and 1 for each 10 year age group. Standardised rates were also obtained separately for males, females, and combined populations, using the Punjab state 1991 population census data. Rates were also estimated according to UK 2000 population data. Ninety five per cent confidence intervals (95% CI) of prevalence and incidence rates of ulcerative colitis were estimated under the assumption that the distribution of cases followed a Poisson probability model. RESULTS: A total population of 51 910 were screened from January to March 1999. We identified 147 suspected cases and of these 23 were finally established as ulcerative colitis cases, giving a crude prevalence rate of 44.3 per 100 000 inhabitants (95% CI 29.4-66.6). A second visit to the same areas after one year identified 10 suspected cases in a population of 49 834. Of these, three were confirmed as "definite" ulcerative colitis giving a crude incidence rate of 6.02 cases per 100 000 inhabitants (95% CI 1.2-17.6). CONCLUSIONS: This is the first population based study from India reporting on the incidence and prevalence of ulcerative colitis. The disease frequency is not much less than that reported from Europe and North America.     

Prevalence of ulcerative colitis in the Israeli kibbutz population

We carried out an epidemiological study of ulcerative colitis in 279 Israeli kibbutzim (121,403 population). The prevalence on December 31, 1987 was 121.08 per 100,000 population. When the data were stratified according to ethnic groups, the highest point prevalence was found in Israeli-born Jews (220.56 per 100,000 population), more than in Asian-African-born, or European-American-born kibbutz members (139.20 and 78.73 cases per 100,000 population, respectively). There were 68 men and 78 women (ratio of 0.87). The average age of the patients in the year of this survey was 46 years; it was 35 years at the time of diagnosis. Proctitis was found in 57%, left-sided colitis in 12%, and substantial or total colitis in 31%. Relapse at pregnancy was demonstrated in seven patients, and remission in one. Family history of a first-degree relative with inflammatory bowel disease was documented in three patients (2%). Probable complications of ulcerative colitis were observed in 38 (26%), anemia in 13 (9%). One patient (0.7%) with rectal cancer, also had breast cancer. We suggest that the impressive increase in ulcerative colitis prevalence among Israeli and Asian-African-born, in comparison with European-American-born kibbutz members, points toward a role of environmental factors in the etiology of this disease.     

Lymphocytic colitis: a retrospective clinical study of 199 Swedish patients

BACKGROUND: Lymphocytic colitis is characterised by chronic diarrhoea and specific microscopic changes in a macroscopically normal colonic mucosa. We report clinical features and treatment outcome in a large patient cohort. METHODS: Patients were searched for in 24 Swedish gastroenterology clinics. The biopsy material was reassessed using strict histopathological criteria. Clinical data were obtained from medical notes. RESULTS: Lymphocytic colitis was diagnosed in 199 cases. The female:male ratio was 2.4:1. Median age at diagnosis was 59 (48-70) years. The most frequent symptoms were diarrhoea (96%), abdominal pain (47%), and weight loss (41%). The course was chronic intermittent in 30% of patients, chronic continuous in 7%, and a single attack in 63%, and in these cases the disease duration was 6 (4-11) months. Seventy nine (40%) patients reported associated diseases, of which thyroid disorders, coeliac disease, and diabetes mellitus were the most common. In 34 first or second degree relatives of 24 (12%) patients, a family history of ulcerative colitis, Crohn's disease, collagenous colitis, or coeliac disease was reported. Drug induced disease was suspected in 19 (10%) patients. A non-significant peak of disease onset was seen in December-January. More than 80% of treated patients improved on corticosteroids, including budesonide. CONCLUSIONS: A family history of other bowel disorders is a new finding. The sudden onset and single attack of limited duration may support a possible infectious cause in some cases. Drugs may cause lymphocytic colitis.     

Are lower gastrointestinal investigations necessary in patients with coeliac disease?

BACKGROUND: Colonoscopy may be indicated in patients with coeliac disease who present with iron deficiency anaemia or in coeliac disease patients who have persisting diarrhoea despite being on a gluten-free diet. However, there are limited data to support this approach. METHODS: We prospectively recruited patients who were found to have coeliac disease, having been referred with newly diagnosed iron deficiency anaemia. We also recruited a second group of patients with known coeliac disease. These patients had persisting diarrhoea despite being on a gluten-free diet for 6 months. All patients had colonoscopy and were matched with controls (without coeliac disease) who had similar indications for colonoscopy. RESULTS: Ninety-eight consecutive new patients with coeliac disease and concurrent iron deficiency anaemia had colonoscopy performed. Twelve (12.2%) had pathology, three of which were carcinomas. This diagnostic yield was not significantly different from the findings in the control group 62/362 (17.1%) P=0.24. In coeliac disease patients with persisting diarrhoea (n=37), the diagnostic yield at colonoscopy was 1/37 (2.7%). This was significantly lower than our findings in the control group with chronic diarrhoea 55/390 (14%) P=0.05. CONCLUSION: Colonoscopy should be considered in patients with coeliac disease (over the age of 45 years) who present with iron deficiency anaemia. Whilst, for coeliac disease patients with persisting diarrhoea (on a gluten-free diet) in the absence of sinister symptoms, a flexible sigmoidoscopy may be the initial investigation in order to exclude microscopic colitis. However, further larger prospective studies are required to evaluate this approach.     

Gastrointestinal involvement in Beh?et's syndrome: a controlled study.

OBJECTIVE: To make a retrospective and prospective analysis of the frequency of symptomatic inflammatory bowel disease in patients with Behçet's syndrome (BS). METHODS: The medical records of the first 1000 patients with BS were reviewed retrospectively for past or present history of diarrhoea. The past and present history of diarrhoea was also elicited prospectively among 147 consecutive patients with BS and 78 diseased controls (42 with rheumatoid arthritis, 17 with systemic lupus erythematosus, seven with seronegative spondylarthropathy, and 12 with miscellaneous rheumatic diseases). Inflammatory mucosal changes were sought in rectal biopsy specimens from 75 patients with BS, 47 diseased controls (29 with nephrotic syndrome, eight with rheumatoid arthritis, six with familial Mediterranean fever, and four with ankylosing spondylitis), and 14 patients with ulcerative colitis. RESULTS: In chart review there were only seven Behçet's patients with diarrhoea; none of them had inflammatory bowel disease. In the prospective survey there were no significant differences between the BS and control groups in the past and present history of diarrhoea. There were no significant differences in the rectal mucosal histology between patients with BS and controls, while patients with ulcerative colitis showed pronounced differences. CONCLUSION: Symptomatic inflammatory bowel disease is not common in BS patients from Turkey.     

Allergic proctitis, a clinical and immunopathological entity.

Patients with isolated ulcerative proctitis form a heterogeneous group. Some may develop ulcerative colitis, others have a limited, benign disease. Twelve patients with isolated proctitis with a mean course of seven years were studied. All patients had a typical clinical picture consisting of a mild and intermittent course of the disease with the presenting symptom of rectal blood loss. At endoscopic examination the inflammatory process was limited to the rectal and distal sigmoid colonic mucosa with a clear upper border beyond which the mucosa of the sigmoid colon was normal. Histologically the mucosal biopsy specimens of the affected rectum resembled those of ulcerative colitis. However, in contrast with proctitis on the base of ulcerative colitis or Crohn's disease, immunoperoxidase staining revealed a markedly increased number of IgE containing cells in the lamina propria of rectal mucosa biopsies. As an IgE-mediated immune mechanism was considered to play a role in this type of proctitis, eight of the 12 patients were treated with oral administration of disodium cromoglycate (DSCG). All patients were improved by the drug. The remaining four patients with mild proctitis did not require treatment. We concluded that, in patients with isolated proctitis on clinical and immunopathological criteria, a group can be separated which responds to DSCG, a condition for which we suggest the name 'allergic proctitis'.     

Impact of bile acid malabsorption on steatorrhoea and symptoms in patients with chronic diarrhoea

OBJECTIVE: Bile acids are important for fat absorption. The relationship between bile acid malabsorption and steatorrhoea and gastrointestinal symptoms in patients with chronic diarrhoea has only been studied on a limited scale. DESIGN: Ninety-four patients referred for chronic diarrhoea were prospectively investigated with the 75SeHCAT test, a faecal fat excretion test and registration of symptoms in addition to the standard clinical work-up. METHODS: The correlation between the 75SeHCAT value and the faecal fat excretion was calculated for different groups of patients. Symptoms were registered in a questionnaire over a period of seven consecutive days. RESULTS: Forty-two patients had a 75SeHCAT value < 10%. Mild steatorrhoea was common in patients with non-organic bile acid malabsorption (50%) and in patients with functional diarrhoea (38%). There was no correlation between low 75SeHCAT values and steatorrhoea, although some patients with severe organic disease had a concomitant malabsorption of fat and of bile acids. In coeliac disease, severe steatorrhoea was common even in patients with high 75SeHCAT values. Patients with bile acid malabsorption had more frequent (P < 0.008) and looser (P= 0.0021) stools compared with patients with functional diarrhoea. There was no difference in abdominal pain, distension or flatulence. CONCLUSION: Mild steatorrhoea is common in both non-organic bile acid malabsorption and functional diarrhoea. The 75SeHCAT value cannot predict the risk of steatorrhoea. The high prevalence of bile acid malabsorption in patients with chronic diarrhoea and the absence of specific symptoms, except frequent and more liquid stools, indicates that the 75SeHCAT test should be performed early in the investigation of these patients.     

Inflammatory bowel disease in the rural Indian subcontinent: a survey of patients attending mission hospitals

39 missionaries working at 38 separate mission hospitals or clinics in Bangladesh. India, Nepal and Pakistan completed questionnaires about their clinical practice during the previous year, 1980. Data were collected about gastrointestinal disorders, including coeliac disease, tropical sprue, bloody diarrhoea, amoebiasis, typhoid, cholera, inflammatory bowel disease and diverticular disease. More than 386,000 out-patients and over 56,000 in-patients were treated with an estimated 12,272 cases of bloody diarrhoea, 7,310 of amoebiasis, 2,113 of typhoid and 872 cases of intestinal tuberculosis, 74 cases of inflammatory bowel disease were diagnosed, of which 56 were ulcerative colitis and the remainder were said to have Crohn's disease. Surgery was performed in 28 hospitals, but only 10 (26%) had a histology service. Inflammatory bowel disease appears to be a relatively more common cause of diarrhoea in the Indian subcontinent than in sub-Saharan Africa (z = 5.47, p less than 0.001). The proportion of patients with bloody diarrhoea who have ulcerative colitis Crohn's disease was similar throughout the region. The rate of cases having ulcerative colitis rather than Crohn's disease was greater in India (z = 3.1, p less than 0.005), and in Bangladesh (z = 3.2, p less than 0.005), than in Pakistan (z = 1.28, NS) or Nepal and Bhutan (z = 0, NS). The relative risk of Indians developing ulcerative colitis rather than Crohn's disease is 2.6 (95% confidence limits 1.4-4.8, NS). This may reflect diagnostic difficulties in distinguishing Crohn's disease from intestinal tuberculosis, but it may also shed light on similar differences now being reported in migrant groups in Western Europe.     

Rectal biopsy and precancer in ulcerative colitis

Forty-seven patients with ulcerative colitis subjected to elective proctocolectomy were investigated with regard to the occurrence of precancerous changes in the rectal biopsy and the operation specimen. In the rectal biopsy from seven patients precancerous lesions were found and in the operation specimens from these patients precancer was also found in other parts of the colon. In five of these patients the precancer was associated with carcinoma and in four of the patients the tumour had not been detected before operation. It is concluded that rectal biopsy is of great value in patients with ulcerative colitis for detection of early cancer and patients at risk of developing a colitis carcinoma.     

Acute mesenteric infarction: an important cause of abdominal pain in ulcerative colitis

We present four cases of acute mesenteric infarction in patients with active ulcerative colitis: one presenting prior to the diagnosis of ulcerative colitis, two at the time of diagnosis, and one many years after the diagnosis had been made. Intestinal ischaemia is an important part of the differential diagnosis in patients with ulcerative colitis presenting with abdominal pain. Conversely, in patients presenting with bloody diarrhoea after mesenteric ischaemia, ulcerative colitis should be considered.     

Colorectal disease in liver allograft recipients -- a clinicopathological study with follow-up

OBJECTIVE : To determine the spectrum and outcome of colorectal diseases occurring in adult liver allograft recipients. DESIGN : A retrospective cohort analysis of clinical, microbiological and histopathological data regarding colorectal disease. PATIENTS : Forty three out of 302 adult primary liver allograft recipients were transplanted and followed up (at median 42 months) at a tertiary referral centre/teaching hospital. RESULTS : Out of 302 patients, 43 (14%) were investigated (by endoscopy and/or laparotomy) for symptoms of colorectal disease after orthotopic liver transplantation. The symptoms were: diarrhoea (n = 31); per-rectal bleeding (n = 5); and symptoms relating to pre-transplant ulcerative colitis (n = 7). Among the patients without known ulcerative colitis, per-rectal bleeding occurring early after orthotopic liver transplantation was most commonly caused by cytomegalovirus colitis and carried a poor prognosis. Excluding ulcerative colitis, the commonest causes of diarrhoea were Clostridium difficile, cytomegalovirus infection and medications, particularly during the first 2 months after orthotopic liver transplantation. No cases of colorectal graft-versus-host disease, cryptosporidiosis, amoebiasis, atypical mycobacterial infection or post-transplant lymphoproliferative disease were demonstrated. The activity of pre-transplant ulcerative colitis was unchanged or increased after orthotopic liver transplantation. Two further patients developed new-onset ulcerative colitis after orthotopic liver transplantation. CONCLUSIONS : Ulcerative colitis, C. difficile, cytomegalovirus infection and medications are the commonest colorectal causes of morbidity after orthotopic liver transplantation. Adult liver allograft recipients are, however, unlikely to show certain large bowel diseases encountered in other immunosuppressed groups. Amongst non-ulcerative colitis patients, those presenting with diarrhoea show a good outcome with appropriate management, whereas those with per-rectal bleeding have a more guarded prognosis.     

Expression of the Kp43 (CD 94) receptor by natural killer (NK) cells in ulcerative colitis.

BACKGROUND/AIMS: The presence of natural killer cells in the colon mucosa of patients with ulcerative colitis has not been studied, therefore, the study was designed to investigate the densities of cells expressing CD3+, CD4+, CD8+, CD56+ and the new CD94+ in colon mucosa of active and inactive ulcerative colitis patients. METHODOLOGY: Twenty ulcerative colitis patients, 10 with active disease and 10 with inactive disease, and 10 subjects with a histologically normal rectal mucosa were used as patients and controls. Additionally, a subgroup of 6 patients with active proctitis has been studied. Two biopsy specimens from rectal mucosa were taken for all patients and controls. Two biopsy specimens of proximal colon mucosa of the subgroup of 6 patients were also taken. One biopsy was processed for immunohistochemical studies and another for histologic study. RESULTS: The densities of CD3+, CD16+, CD56+ and CD 94+ were significantly increased in active ulcerative colitis patients compared to inactive subjects (P < 0.001). The increase in the CD4+ and CD8+ was not statistically significant. Patients with inactive ulcerative colitis also presented increased numbers of CD3+, CD56+ and CD94+ cells compared to controls (P < 0.001). In the subgroup of proctitis, the densities of cells expressing all the antigens were significantly lower in the normal mucosa compared to the affected colon (P < 0.001). No differences in the number of lamina propria DC1a+ cells between patients and controls were found. CONCLUSIONS: These findings suggest that natural killer cells are increased in active ulcerative colitis subjects and that the affected mucosa of ulcerative colitis patients with inactive disease is in state of "latent" inflammation. On the other hand, the normal looking mucosa from active ulcerative colitis patients does not differ from the mucosa of control subjects. Therefore, it seems that in ulcerative colitis the immunological alterations are limited to the affected mucosa.     

Metachronous occurrence of collagenous colitis and ulcerative colitis.

Collagenous colitis and ulcerative colitis are distinct disorders. A 67 year old woman with clinical and histological evidence of collagenous colitis had an abrupt symptomatic exacerbation while taking anti-inflammatory treatment with sulphasalazine and prednisone. Repeat colorectal endoscopy showed active mucosal inflammation and colonic biopsy specimens were consistent with active ulcerative colitis. After bowel rest, total parenteral nutrition, intensification of the anti-inflammatory regimen, and withdrawal of non-steroidal anti-inflammatory drugs (which she had taken continuously for osteoarthritis) diarrhoea abated. Colorectal biopsy specimens obtained when the patient's symptoms had improved showed inactive ulcerative colitis with no evidence of collagenous colitis. This may be the first case to be reported of the metachronous association of collagenous and ulcerative colitis.     

Olsalazine versus placebo in the treatment of mild to moderate ulcerative colitis: a randomised double blind trial.

The effect of olsalazine, an analogue of sulphasalazine, consisting of two molecules 5-aminosalicylic acid linked by an azobond has been investigated for the treatment of ulcerative colitis. In a randomised double blind trial we compared 2 g olsalazine with placebo for four weeks. Of the 105 patients, with mild to moderate ulcerative colitis, entered in the trial 52 received olsalazine, and 53 placebo. Treatment had to be terminated prematurely because of untoward effects of olsalazine (mainly diarrhoea) in three patients and treatment failure--that is, increased rectal bleeding in four patients (olsalazine group: one placebo group: three). After four weeks' treatment, a statistically significant improvement in the endoscopic findings in rectum and a positive trend in the reduction of rectal mucus and blood discharge was observed in the patients treated with olsalazine. No statistically significant difference was found for other factors, including stool frequency, consistency, urge to defecate, abdominal pain, and biopsy findings. A comparison between these clinical and endoscopic parameters at study entry and those at study completion (within drug evaluation) showed significant improvement in six of 10 parameters during treatment with olsalazine and in two of 10 during placebo treatment. This difference suggests the significant effect of olsalazine. We conclude that 2 g olsalazine was tolerated as well as placebo, apart from causing diarrhoea in some patients and was slightly superior to placebo during four weeks' treatment of mild to moderate ulcerative colitis. A study with 3 or 4 g olsalazine per day may show a more definite effect.     

Ulcerative colitis in the South African Bantu

Two cases of ulcerative colitis in the Bantu are reported. One patient presented with fulminant acute colitis with toxic dilatation of the colon and massive rectal haemorrhage, the second with chronic, continuous diarrhoea for over twenty years, culminating ultimately with carcinoma of the colon.The aetiology of ulcerative colitis is discussed, together with the problems of specific diagnosis encountered in a population with a high incidence of parasitic infestation and infective diarrhoea.It is considered that the sparseness of reports and apparent rarity of this disease in the Bantu may reflect a failure of detection rather than a true infrequent occurrence. The natural incidence of the disease may be on the increase.