PROLONGED SURVIVAL AND LATE PRESENTATION OF VERTICALLY TRANSMITTED HIV INFECTION IN CHILDHOOD

806 TABLE I-PATIENT

TOPICAL CYCLOSPORIN AND PSORIASIS

SIR,-Cyclosporin, at a low dose of 3 mg/kg daily, clears severe psoriasis." Therefore, we investigated the efficacy of topical cyclosporin in chronic plaque psoriasis. In view of the dose-related nephrotoxicity associated with systemic cyclosporin, a topical preparation for dermatological disease would be therapeutically advantageous. 6 patients (4 female, aged 22-65 years) with chronic plaque psoriasis entered a double-blind study. The oral solution of cyclosporin (’Sandimmun’, Sandoz) was made up 2% w/w in an ointment (Unguentum Merck) and applied twice daily to a psoriatic plaque on an arm or leg for 4 weeks. A placebo solution in the same ointment was applied twice daily to a plaque on the opposite limb, also for 4 weeks. The plaques were assessed each week for desquamation, induration, and erythema, and blood pressure, whole blood cyclosporin levels, and renal function were also monitored. The response to placebo or cyclosporin at the end of the study was similar in all patients. No systemic cyclosporin absorption, or change in renal function or blood pressure was

1:IMMUNOLOGICAL FUNCTION

*Cimetidine from

Sept 6,1983. tPhytohaemagglutinin response (stimulation index); normal

> 20.

t% of normal control. §Normal > 1 6. TABLE 11-HAEMATOLOGICAL AND IMMUNOLOGICAL

INVESTIGATIONS

(1986)

detected. Because of the highly lipophilic nature of cyclosporin and its beneficial effect in psoriasis when given systemically, we were surprised that there was no response when the drug was applied topically at this concentration in a suitable ointment base. One explanation may be that cyclosporin is not absorbed into the epidermis or dermis of psoriatic plaques. However, cyclosporin, when applied topically in the same ointment that we used, does inhibit the patch-test response to allergensalbeit in only 20% of subjects. A second explanation, if absorption took place, is that the therapeutic effect of systemic cyclosporin may be due to metabolites. We are currently investigating the epidermal and dermal uptake of cyclosporin and its metabolites in psoriasis. We thank Sandoz for supplying cyclosporin, Dr D. W. Holt of New Cross Hospital poisons unit for estimation of cyclosporin levels in blood and ointment, and the pharmacy department of St Mary’s Hospital. C. E. M. G. is a Wellcome research training fellow and L. F. receives grants from the Wellcome Trust and Skin Disease Research Fund.

London W2 1NY

C. E. M. GRIFFITHS A. V. POWLES B. S. BAKER LIONEL FRY

Department of Immunology, Landspitalinn, Reykjavik

H. VALDIMARSSON

Department of Dermatology, St Mary’s Hospital,

CEM, Powles AV, Leonard JN, et al. Clearance of psoriasis with low dose cyclosporin. Br Med J 1986; 293: 731-32. 2. Harper JI, Keat ACS, Staughton RCD. Cyclosporin for psoriasis. Lancet 1984; ii: 1. Griffiths

981-82. 3. Van Joost TH, Heule F, Stolz

E, et al. Short term use of cyclosporin A in severe psoriasis. Br J Dermatol 1986; 114: 615-20. 4. Marks J. Psoriasis. Br Med J 1986; 293: 509. 5. Aldridge RD, Sewell HF, King G, Thompson AW. Topical cyclosporin A m nickel contact hypersensitivity: Results of a preliminary clinical and immunohistochemical investigation. Clin Exp Immunol 1986; 66: 582-89.

PROLONGED SURVIVAL AND LATE PRESENTATION OF VERTICALLY TRANSMITTED HIV INFECTION IN CHILDHOOD

SIR,-Not all babies born

to mothers infected with human virus immunodeficiency (HIV) will themselves be infected but if they are, symptoms usually develop by 6 monthsl.2 and most die within 2 years.3 Survival to age 36 months or more is rare and the prognosis of AIDS after vertical transmission of HIV is generally bleak.3 We describe here the clinical and immunological fmdings in a symptomless HIV carrier and her two sons 4 and 8 years after presumed vertical HIV transmission. The first child (patient 1), born in the UK, presented in 1982 aged 3 months with failure to thrive, diarrhoea, eczema, hepatosplenomegaly, and lymphadenopathy. The pregnancy had been normal and he had been breast fed for 2 months. On further

investigation at 7 months hyper-IgE syndrome was suspected (serum IgE 740 IU/ml ; normal 0-30). He also had hypergammaglobulinaemia and an inverted CD4/CD8 T cell ratio (table I). A

I

Normal values (as lower limit of normal,

I mean

t

i

SD, or normal range for age) shown in

parentheses.

chest

X-ray revealed perihilar infiltrates. Biopsy confirmed the Lymph node biopsy suggested a non-specific dermatopathic adenopathy (in retrospect classified as HIV-related lymphadenopathy stage I4)_ Specific IgE antibodies and skin-prick tests were weakly positive for egg and he was treated with a milk and egg free diet, prophylactic antibiotics, ascorbic acid, and cimetidine (for the hyper-IgE syndrome). He made good progress over the next 4 years; his eczema improved but the interstitial pulmonary changes and lymph node, liver, and spleen enlargement have persisted. No viruses or opportunistic organisms have been isolated and Pneumocystis carinii antibodies were negative. IgE levels fell, IgG rose, and neutrophil function returned to normal, but the eczema.

CD4/CD8

ratio remained low. In 1986 he

was

found

to

be HIV

antibody positive (confirmed by western blotting). He continues to do well. The boy’s half-brother (patient 2), now aged 8, was born in Africa. He was HIV antibody positive when tested in 1986. His birth and neonatal development were normal and he had been breast fed for 18 months. He had had no blood transfusions, hospital admissions, or infections before he left Africa at the age of 2 years. At 3 years he had herpes zoster and at 6 years he had developed a chronic cough with recurrent chest infections. He was on the 50th centile for height and weight. He had an interstitial pneumonia and mild lymphadenopathy but no hepatosplenomegaly. No opportunistic organisms or viruses were detected and P carinii antibodies were negative. He had hypergammaglobulinaemia with a low CD4/CD8 ratio (table 11). He remains well. The 24-year-old mother was HIV antibody positive and was symptom-free. She had had a herpes zoster infection 6 months before investigation. She had hypergammaglobulinaemia and an inverted CD4/CD8 ratio. The younger boy’s father is HIV seronegative and has been in the UK since 1964. The mother had previously been married in Africa and had a stillborn child and a healthy boy (patient 2) by her first marriage. She had two blood transfusions in Africa, one at the time of her stillbirth and the second following the delivery of patient 2 (his father lives abroad). This African family with HIV infection presents several interesting features. It seems probable that both children were

807 infected with HIV by vertical transmission. Retrospective studies of HIV seropositive mothers with one child with vertically transmitted AIDS reveal a 65% frequency of HIV transmission in subsequent pregnancies.6 However, the rate of vertical transmission of HIV from symptomless carriers is unknown. The children we studied had no risk factors for HIV infection other than vertical transmission at delivery. Transmission of HIV via breast milk or horizontally is very unusual. The woman could have been infected by her first husband or via the first blood transfusion in Africa. The early clinical symptoms of patient 2 could, in retrospect, be considered typical of neonatal HIV infection. His brother, 85 years after infection, also has signs of HIV infection and both children can be classified as HIV infection group IVE (ie, beyond persistent

generalised lymphoadenopathy but not having full-blown AIDS). Patient 1 has been treated with cimetidine at a dose of 30 mg/kg daily from the age of 10 months. Cimetidine has non-specific immunostimulatory effects;8 it stimulates neutrophil migration in vitro,’ although the exact mode of action is still unknown. It is tempting to ascribe this patient’s benign course, over 4 years, to the prophylactic antibiotics and/or cimetidine, but this does not explain the benign course in the brother who, 8-5 years after presumed vertical HIV infection, is doing well. Both cases are in contrast to previous bleak reports of the prognosis of vertical HIV infection. The fact that it took 8 years to identify a high-risk but symptomless HIV carrier is worrying. Antenatal screening for women at risk, combined with counselling, must be considered. HIV antibodies should be sought in children with unexplained non-specific symptoms of immunodeficiency from families with increased risk. Our family does suggest that children, even after vertical HIV infection, can survive for a long time and may improve clinically and immunologically on vigorous anti-infective therapy.

St Mary’s Hospital, Portsmouth

Department of Immunology, Hospital for Sick Children, London WC1.

D. A. KELLY R. J. HALLETT A. SAEED G. MORGAN R. J. LEVINSKY S. STROBEL

Acquired immunodeficiency syndrome in infants. Am J Dis Child 1983, 137: 825-27. 2. Shannon KM and Ammaan AJ. Acquired immunodeficiency syndrome in childhood. J Pediatr 1985; 105: 332-42. 3 Anon. Update on acquired immunodeficiency syndrome (AIDS)—United States. MMWR 1984; 33: 337. 4 Pallesen G, Gerstaff J, Mathiesen L. Stages in LAV/HTLVIII lymphadenitis I: Histological and immunohistological classification. Scand J Immunol 1987; 25: 83-91. 5. Morgan G, Hendnckse W, Harvey B, et al. Treatment of the hyper-IgE syndrome with cimetidine. In: Vossen J, Griscelli C, eds. Progress in immunodeficiency research and therapy II. Amsterdam: Excerpta Medica, 1986. 217-23. The epidemiology of pediatric acquired 6. Rubinstein A, Bernstein L immunodeficiency syndrome. Clin Immunol Immunopathol 1986; 40: 115-21 7. Classification system for human T lymphocyte virus type III lymphadenopathyassociated virus infections. MMWR 1986; 35: 334-38. 8. Vickers MR. Cimetidine and the immune system. In: Cimetidine in the 80s Edinburgh Churchill Livingstone, 1981: 238-46. 1. Rubinstein A

ROUTINE TESTS FOR HIV ANTIGEN iR,—/s

i’UlaITl ei ai ana several

correspunuenis

in

your issue 01

March 7 have shown, tests for HIV antigen are being used in research investigations and there is likely to be pressure for them to be used for screening blood donors. This would be in addition to the anti-HIV tests used by blood transfusion services. Tests for antibody to HIV are likely to remain the best method of identifying HIV carriers except during the period’soon after infection before anti-HIV has developed. This period may last for a matter of weeks or sometimes months, and some, but not all, instances of post-transfusion HIV infection would certainly be prevented if tests for antigen were introduced to supplement tests for antibody. However, the antigen tests would not be sensitive enough to detect all infectious anti-HIV negative donations. The questions which have to be answered are what benefit in terms of extra safety for recipients would come from screening all donations for HIV antigen and would this benefit justify the expenditure

required? So far only two cases have been reported where an infectious but anti-HIV negative donor has infected recipients before seroconver-

sion. One case was in Colorad02 and the other was reported recently from Glasgow.3 In the UK 70-80 % of donors give blood more than once in a year, which means that seroconversion in a donor can often be detected within 6 months of it happening. Donations given on the occasion before seroconversion is detected are those most likely to be infectious, even though negative for anti-HIV. The recipients of these donations can be tested to see whether they have been infected, making it possible to assess the extent of the danger from HIV positive, anti-HIV negative donations without waiting, perhaps years, for recipients to develop AIDS. So far in the UK only the one instance referred to of an infectious, but anti-HIV negative, donation being used has been identified. The rarity of such an event is due to the very low prevalence (1 in 50 000) of anti-HIV positive donors in the UK, and this depends on the vigour with which the "self-exclusion" of high-risk donors is promoted. The great majority of high-risk potential donors do exclude themselves; nevertheless, about 90 % of the donors who are found to be anti-HIV positive belong to high-risk groups. Thus even greater efforts to dissuade persons belonging to high-risk groups from giving blood might achieve the same end as screening all donations for HIV antigen, but at very much less cost. National Blood Transfusion Service, North London Blood Transfusion Centre, Edgware, Middx HA8 9BD

MARCELA CONTRERAS JOHN A. J. BARBARA

JP, Laurian Y, Paul DA, et al. Serological markers in early stages of human immunodeficiency virus infection in haemophiliacs. Lancet 1986; ii: 1233-36. Centers for Disease Control. Transfusion-associated human T-lymphotropic virus type III/lymphadenopathy-associated virus infection from a seronegative

1. Allain 2.

donor—Colorado. MMWR 1986; 35: 380-91 3. Crawford RJ, Mitchell R, Bumett AK, Follett EAC. Who may give blood? Br Med

J

1987; 294: 572.

MAGNETIC RESONANCE IMAGING AND SMOOTH PERIVENTRICULAR HIGH-SIGNAL AREAS itt,—me expiananon

oi

penvenmcuiar nign-signai areas,

demonstrated by magnetic resonance imaging (MRI), is controversial. Initially regarded as synonymous with multiple sclerosis, such areas can be a normal finding in 30% of healthy subjects aged over 60,1 but have also been considered a marker of cerebrovascular disease and a useful aid in differential diagnosis between vascular dementia and Alzheimer’s diseased A comparison of post-mortem MRI of a brain, before and after fixation, with neuropathological findings provides a possible explanation for

periventricular high-signal areas. An 80-year-old man died from respiratory failure caused by pneumonia. Immediately after necropsy, 8 h after death, the brain was removed and pre-iixation images were taken with a 0 15 T resistive imager. Coronal T2 weighted images (SE2000/80) showed characteristic periventricular high-signal areas that were smooth, confluent, and symmetrical, especially at the anterior and posterior horns of the lateral ventricles. These fean1res were still present but less obvious after the brain had been fixed in 4% formaldehyde in saline for three weeks. The cerebral ventricles were moderately dilated but the cortex was not atrophic. The brain was sectioned into 1 cm coronal slices, in the same plane as MRI, for histology. The fixed brain did not have any macroscopic abnormality. The circle of Willis was normal and the basal vessels, although sclerosed, were only minimally atheromatous. There was no evidence of cerebral infarction or cortical atrophy. The regions at the anterior aspect of the frontal horns and the posterior aspect of the occipital horns were paler than the remainder of the white matter. On microscopy, the neuropil at the angle of the frontal horn was of looser texture than the adjacent centrum semiovale and corpus callosum. As a consequence there was pallor of myelin staining and a greater amount of extracellular space between axons. These changes lay beneath a focally deficient ependyma. The ependymal changes, however, were not those of granular ependymitis,3as there was no evidence of underlying gliosis High-signal areas in T2 weighted images are caused by increased water or decreased lipid content and are commonly seen around the ventricles in patients with demyelination, and in cerebrovascular disease. In these cases there are focal lesions with specific