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T. D e l h a a s �9 M . Jansen �9 G. Sinnelna J. E. A. R. D e Schryver �9 K. de M e e r

Steroid-resistant inflammatory bowel disease: a patient with non-compliance in the hospital

Received: 1 May 1997/Accepted 26 August 1997

evaluating the effect of intravenous steroid administration. Instead of leaving more elaborate tests for the very last resort, it was decided to investigate whether this patient was steroid-resistant or had a steroid malabsorption. Confronting the patient with the results of the laboratory tests, however, she finally admitted to non- compliance.

In conclusion, in case of therapeutic non-responsiveness, patient non-compliance must always be considered before rare possibilities are investigated. This rule also holds in conditions where all odds are against this possibility, as demonstrated by this case report.

Sir: We present a patient with inflammatory bowel disease in whom 2 months of high-dose oral corticosteroids, a frequently used drug with clinical response within 3 weeks in the majority of cases [3], failed to induce either improvement or side-effects. Since all odds were against non-compliance, we first investigated other causes of non-response. However, eventually she was found to dispose her medication.

The patient, a previously healthy 11-year-old girl, presented with typical signs of inflammatory bowel disease: marked diarrhoea (> 6 stools/day, including nightly), rectal blood loss, abdominal pain, and severe weight loss. Laboratory tests showed anaemia, elevated ESR and hypo-albuminaemia. Stool examination showed occult blood and high ~l-antitrypsin content. Endoscopic evalua- tion including biopsies, restricted to the rectosigmoid due to extreme pain, showed severe inflammation with patchy and confluent ulcerations. Stool cultures were negative for Salmonella, Shigela, Yersinia and Campylobacter. Prednisone (2 mg/kg/day orally in three equally divided doses), 5'-aminosalicylate and hydrocortisone enemas were started. During the following weeks, however, neither therapeutic nor side-effects of the steroid medi- cation were seen. The possibility of non-compliance was discussed repeatedly, but was rejected by nurses, doctors, and the clinical psychologist: the patient had an accurate knowledge of her disease and of the treatment regimen, and was strongly motivated to recover. Psychological and social development (stable family) before the onset of the illness had been quite favourable. During the deterioration of the physical symptoms, anxiety and depressive spells increased, but these were seen as normal emotional counterparts of the acute symptoms.

Thus, the possibility of either steroid malabsorption or steroid resistance was investigated first by means of: (1) prednisolone top level after supervised intake of prednisone; (2) fasting serum ACTH and cortisol levels in the patient; and (3) serum cortisol levels and overnight dexamethasone suppression test in both parents. Based on the results of these laboratory tests, however, the diagnosis of non-compliance appeared inevitable and was finally admitted by the patient: she flushed both her oral medication and enemas through the toilet in her room. Upon this disclosure, intravenous steroid medication (2 mg/kg/day prednisolone sodiumsuccinate in three equally divided doses) was started. Within 3 days the defaecation frequency decreased to twice a day and rectal blood loss disappeared.

The possibility of non-compliance should always be considered in case of non-response to medication. In adolescents with acute lymphoblastic leukaemia or Hodgkin disease non-compliance with prednisone medication is reported to be as high as 52% [2]. Defects in steriod responsiveness on the other hand, are relatively rare and occur in < 5% of the population [1]. However, in terms of psychosocial development, family background and coping, the odds were against non-compliance in our patient. Moreover, since she was nursed in a glass-walled room giving ample opportunity for observation, the possibility of non-compliance was initially denied, and valuable time was lost. Non-compliance could have been detected at an early stage of the therapeutic dilemma by either careful supervision of the intake of the oral medication or by

References

1. Lamberts SWJ, Huizenga ATM, DeLange P, Jong FH de, Koper JW (1996) Clinical aspects of glucocorticoid sensitivity. Steroids 61:157-160

2. Tamaroff MH, Festa RS, Adesman AR, Walco GA (1992) Therapeutic adherence to oral medication regiments by adoles- cents with cancer. II. Clinical and psychologic correlates. J Pediatr 120:812-817

3. Werlin SL, Grand RJ (1977) Severe colitis in children and adolescents: Diagnosis, course, and treatment. Gastroenterology 73:828-832

T. Delhaas �9 J. E. A. R. De Schryver �9 K. de Meer ([~) Department of Paediatric Gastroenterology, University Children's Hospital, 'Het Wilhelmina Kinderziekenhuis', P.O. Box 18009, NL-3501 CA Utrecht, The Netherlands, Tel.: ( + 31)-30-2320911, Fax: (+ 31)-30-2334825

M. Jansen Department of Endocrinology, University Children's Hospital, Utrecht, The Netherlands

G. Sinnema Department of Psychology, University Children's Hospital, Utrecht, The Netherlands

G. Lat ini �9 E. Rosa t i

Transient neutropenia may be a risk of treating preterm neonates with high doses of recombinant erythropoietin

Received: 21 July 1997/Accepted: 2 September 1997

Sir: Many reports have confirmed that recombinant human erythropoietin (rHuEpo) administration to preterm neonates can accelerate erythropoiesis and thereby reduce requirements for blood transfusion [3, 4]. The doses of rHuEpo used in published studies of preterm infants have ranged from 300~1200 U/kg per week, and no serious adverse dose-dependent or dose-independent effects have been reported.

In haematopoietic progenitor cell cultures [2] and in neonatal animals [1] very high doses of Epo can reduce neutrophil production from granulocyte/macrophage progenitors. However

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Table 1 Clinical data and changes in neutrophil count Case 1 Case 2 Case 3

(900 U/kg/week) (1200 U/kg/week) (1200 U/kg/week)

Gestational age 31 32 29 (weeks)

Birth weight 1480 1500 1150 (g)

Age at onset rHuEpo 18 17 32 (days)

Neutrophil count 2130 4140 6610 (cells/lal) at onset rHuEpo

Neutrophil count 1510 1350 1330 (cells/gl) after six doses of rHuEpo

Neutrophil count 790 600 - (cells/gl) after 12 doses of rHuEpo

hyporegenerative neutropenia has not been a consistent feature of rHuEpo treatment in preterm neonates [3-5]. We recently began a rHuEpo dose-finding study in 3-week-old preterm infants with birth weights <1500 g born at a gestational age of <32 weeks. The infants are receiving either 0 U (controls), 600 U, 900 U, or 1200 U of rHuEpo/kg per week subcutaneously. To date we have enrolled six subjects, and the purpose of this letter is to report the occurrence of neutropenia in all three patients receiving the highest rHuEpo dosage (one receiving 900 U/kg and two receiving 1200 U/kg). The values are given in Table 1.

In all three cases, we excluded other causes of neutropenia such as sepsis, alloimmune neutropenia, and Kostman syndrome. Patients remained well despite their very low blood neutrophil concentrations. Neutrophil counts increased in all following discontinuation of rHuEpo administration. Although the number of patients we report is admittedly small, we wish to caution readers that neutropenia might need to be considered as a risk when preterm infants are treated with higher doses (>900 U/kg/ week) of rHuEpo.

References

1. Christensen RD, Liechty KW, Koenig JM, Schibler KR, Ohls RK (1991) Administration of erythropoietin to newborn rats results in diminished neutrophil production. Blood 78:1241- 1246

2. Christensen RD, Rothstein G (1992) The effect of erythropoietin on production of neutrophils and macrophages from G-CSF- responsive progenitors of fetal and adult origin. Am J Hematol 39:108 112

3. Mayer RF, Obladen M, Scigalla P, Linderkamp O, Duc G, Hieronimi G, Hallyday HL, Versmold HT, Moriette G, Jorch G, et al (1994) The effect of epoetin beta (recombinant human erythropoietin) on the need for transfusion in very-low-birth- weight infants. European Multicentre Erythropoietin Study Group. N Engl J Med 330:1173-1178

4. Widness JA, Gleason CA, Bifano EM, Millard DD, Davis CB, et al (1995) Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusion in very low birth weight preterm infants. Pediatrics 95:1-8

5. Williamson P, Griffiths G, Norfolk D, Levene M (1996) Blood transfusion and human recombinant erythropoietin in prema- ture newborn infants. Arch Dis Child 75:F65 F68

G. Latini ([]) �9 E. Rosati Neonatal Intensive Care Unit, Azienda Ospedaliera "A. Di Summa", Piazza Di Summa, 1-72100 Brindisi, Italy, Tel.: + 39-831-510459 Fax: + 39-831-523917