691
significant. Thus, in the setting we described, duration of fever before presentation remains a factor linked to malarial origin of the fever. The clustering of high parasitaemia, even among afebrile controls, during the wet season remains largely unexplained. Brabin’ has used methodology comparable with ours to predict low birth rate due to malaria, especially in primiparae. Lindsay et aF have reported findings on the seasonality of malaria in the Gambia similar to those we described in Niger. We are not in essential disagreement with Dr Peters and Dr Gray and basically concur with their main conclusion on "... presumptive treatment of all febrile children, especially those with fever of short duration ... during the rainy season". What we tried to do is to provide additional criteria, permitting focus on smaller subgroups at highest risk. We did not adopt the sensitivity, specificity, predictive value approach, however desirable that may be in principle, chiefly because a satisfactory definition of a "true" malaria attack remains to be found. The fact that those who have commented on our article tend to cite the same few references also suggests a pressing need for further clinico-epidemiological studies. We appreciate the remarks of Dr Van den Ende and colleagues. All the descriptive data needed are available (ref 11 in our article). However, our Lancet contribution was an epidemiological approach to risks at a community level (table III, last column) to rationalise the management of the most common situations. Our main conclusion was an emphasis on primary importance of season (table I) and on the "unclear" origin of fever (table n) when deciding to treat or not to treat for malaria children presenting with fever. Our findings lead to a focus on high risk groups (V-VIII in table Hi), all clustering during the rainy season. During the dry season, the predictive value of fever was higher for controls than for cases in our series so it does not seem justified "to treat as malaria all children with fever and without another obvious cause". The ideal management is clearly an individual one, every patient being examined by a doctor, but, in Sahelian conditions, characterised by chronic shortage in medical personnel, diagnostic tests, and drugs, only a small minority of patients can benefit from such facilities. So, a simple, well-validated decision tree, drawing the attention of medical and other front-line health personnel to groups at risk, may be a first step to a more rational approach to the diagnosis and treatment of childhood malaria. As a second step, controlled prospective studies in various settings and within groups defined by our paper are, we agree, needed. More than 1000 cases and controls are not "very small numbers". In some groups, after random selection during a whole annual cycle, the use of criteria proposed in table III sometimes led to few cases (eg, fever of clear origin, of more than 39°C, and lasting for more than 3 days [group
II]. Community Health and Tropical Medicine Unit, University of Geneva School of Medicine, 1211 Geneva, Switzerland
A. ROUGEMONT E. BRENNER
birthweight risk in primiparae as an indicator of J malaria control in pregnancy. Int Epidemiol 1991; 20: 276-83. 2 Lindsay SW, Wilkms HA, Zieler HA, et al Ability of Anopheles gambiae mosquitoes to transmit malaria during the dry and wet seasons in an area of irrigated rice cultivation in The Gambia. J Trop Med Hyg 1991; 94: 313-24. 1 Brabin B An assessment of low
SiR,—Professor Rougemont and colleagues emphasise the importance of the clinical diagnosis of childhood malaria in endemic zones, based on simple clinical criteria and parasitaemia. Their study was done in Niger where malaria transmission is irregular, high during the rainy season and low during the dry season. They suggest studies in areas where malaria transmission is different. Gabon, in equatorial Africa, has continuous high-transmission of Plasmodium falciparum. We have studied the prognostic value of parasite count at time of hospital admission in 69 Gabonese children aged 3-13 years (mean age 6-8) with acute Pfalciparum malaria. 14 (group 1) were comatose with repeated convulsions and met criteria for cerebral malarial 5 (group 2) had had a single convulsion without impaired consciousness, and 50 (group 3) had no neurological symptoms. We also included 47 healthy carriers of malaria infection, recruited from 141 schoolchildren tested for P falciparum by systematic examination of thin blood films (group 4). No child had chemoprophylaxis or antimalarial drugs during the month before the test.
PARASITE COUNTS AND CLINICAL FINDINGS
*(3)
vs
(1)
and
(2) NS, t (4)
vs
(1)and (3) p 100 000/1) or hyperparasitaemia (> 250 000/1) were found in the absence of cerebral malaria (table). In these children, in an endemic equatorial area and with a high level of immunity, parasite counts do not reliably predict the severity of P falciparum infection. Counts are not sufficient to guide treatment--especially the choice between the intravenous quinine required in cerebral malaria and oral therapy. Our results support the importance of a global clinical analysis of malaria infection, as reported by Rougemont et al. Hôpital Saint-Vincent-de-Paul,
DOMINIQUE GENDREL
75674 Paris, France
Faculty of Medicine,
MARYVONNE KOMBILA
Libreville, Gabon
Faculty of Medicine,
DOMINIQUE RICHARD-LENOBLE
Tours
D, Kombila M, Nardou M, Gendrel C, Djouba F, Richard-Lenoble D. Protection against Plasmodium falciparum infection in children with hemoglobin S. Pediatr Infect Dis J 1991, 10: 620-21 2 Philips RE, Solomon T Cerebral malaria in children. Lancet 1990; 336: 1355-60. 1. Gendrel
Chromosomal aberrations defining uveal melanoma of poor prognosis SIR,-Uveal melanoma is the most common primary intraocular malignancy. The estimated 15-year-survival rate after detection of the tumour is 46%.1 As in other malignancies, tumour size and cell type are major risk factors for metastasis. However, we do not know why the location of a uveal melanoma in the ciliary body is one of the most important factors for poor prognosis, even in statistical models with correction for all other risk factors.z°3 We propose that specific chromosomal aberrations explain the difference in survival rates for patients with choroidal or with ciliary-body melanomas. Cytogenetic analysis of uveal melanomas revealed monosomy of chromosome 3 and multiplication of chromosome 8q material as non-random chromosomal aberrations.4- These findings have been confirmed by DNA polymorphism studies.’ To date, 34 tumours with data about location are available (table). In uveal melanomas involving the ciliary body, chromosome 3 alleles were lost in 14 (70%) of 20 informative cases. Multiplication of chromosome 8q alleles was found in 14 (74%) of 19 informative cases. Only 2 of 20 informative cases did not have any of these aberrations. By contrast, of 13 choroidal melanomas, monosomy of chromosome 3 was seen in 3 (23%) and multiplication of chromosome 8q in 2 (15%). 10 tumours (77%) in this group did not have any of these aberrations. Differences in the frequency of these aberrations between uveal melanoma with ciliary-body involvement and choroidal melanoma are significant (p 0-011 for loss of chromosome 3 alleles, p = 0-002 for multiplication of 8q alleles; Fisher’s exact test). Thus, loss of chromosome 3 alleles and multiplication of 8q alleles may defme a subgroup of uveal melanoma with poor prognosis. =
692
CHROMOSOMES 3 AND 8 ABERRATIONS IN CILIARY BODY AND CHOROIDAL MELANOMA
TABLE I--ANALYSIS OF LINKAGE DISEQUILIBRIUM
__.
_
.
*p
significant. Thus, in the setting we described, duration of fever before presentation remains a factor linked to malarial origin of the fever. The clustering of high parasitaemia, even among afebrile controls, during the wet season remains largely unexplained. Brabin’ has used methodology comparable with ours to predict low birth rate due to malaria, especially in primiparae. Lindsay et aF have reported findings on the seasonality of malaria in the Gambia similar to those we described in Niger. We are not in essential disagreement with Dr Peters and Dr Gray and basically concur with their main conclusion on "... presumptive treatment of all febrile children, especially those with fever of short duration ... during the rainy season". What we tried to do is to provide additional criteria, permitting focus on smaller subgroups at highest risk. We did not adopt the sensitivity, specificity, predictive value approach, however desirable that may be in principle, chiefly because a satisfactory definition of a "true" malaria attack remains to be found. The fact that those who have commented on our article tend to cite the same few references also suggests a pressing need for further clinico-epidemiological studies. We appreciate the remarks of Dr Van den Ende and colleagues. All the descriptive data needed are available (ref 11 in our article). However, our Lancet contribution was an epidemiological approach to risks at a community level (table III, last column) to rationalise the management of the most common situations. Our main conclusion was an emphasis on primary importance of season (table I) and on the "unclear" origin of fever (table n) when deciding to treat or not to treat for malaria children presenting with fever. Our findings lead to a focus on high risk groups (V-VIII in table Hi), all clustering during the rainy season. During the dry season, the predictive value of fever was higher for controls than for cases in our series so it does not seem justified "to treat as malaria all children with fever and without another obvious cause". The ideal management is clearly an individual one, every patient being examined by a doctor, but, in Sahelian conditions, characterised by chronic shortage in medical personnel, diagnostic tests, and drugs, only a small minority of patients can benefit from such facilities. So, a simple, well-validated decision tree, drawing the attention of medical and other front-line health personnel to groups at risk, may be a first step to a more rational approach to the diagnosis and treatment of childhood malaria. As a second step, controlled prospective studies in various settings and within groups defined by our paper are, we agree, needed. More than 1000 cases and controls are not "very small numbers". In some groups, after random selection during a whole annual cycle, the use of criteria proposed in table III sometimes led to few cases (eg, fever of clear origin, of more than 39°C, and lasting for more than 3 days [group
II]. Community Health and Tropical Medicine Unit, University of Geneva School of Medicine, 1211 Geneva, Switzerland
A. ROUGEMONT E. BRENNER
birthweight risk in primiparae as an indicator of J malaria control in pregnancy. Int Epidemiol 1991; 20: 276-83. 2 Lindsay SW, Wilkms HA, Zieler HA, et al Ability of Anopheles gambiae mosquitoes to transmit malaria during the dry and wet seasons in an area of irrigated rice cultivation in The Gambia. J Trop Med Hyg 1991; 94: 313-24. 1 Brabin B An assessment of low
SiR,—Professor Rougemont and colleagues emphasise the importance of the clinical diagnosis of childhood malaria in endemic zones, based on simple clinical criteria and parasitaemia. Their study was done in Niger where malaria transmission is irregular, high during the rainy season and low during the dry season. They suggest studies in areas where malaria transmission is different. Gabon, in equatorial Africa, has continuous high-transmission of Plasmodium falciparum. We have studied the prognostic value of parasite count at time of hospital admission in 69 Gabonese children aged 3-13 years (mean age 6-8) with acute Pfalciparum malaria. 14 (group 1) were comatose with repeated convulsions and met criteria for cerebral malarial 5 (group 2) had had a single convulsion without impaired consciousness, and 50 (group 3) had no neurological symptoms. We also included 47 healthy carriers of malaria infection, recruited from 141 schoolchildren tested for P falciparum by systematic examination of thin blood films (group 4). No child had chemoprophylaxis or antimalarial drugs during the month before the test.
PARASITE COUNTS AND CLINICAL FINDINGS
*(3)
vs
(1)
and
(2) NS, t (4)
vs
(1)and (3) p 100 000/1) or hyperparasitaemia (> 250 000/1) were found in the absence of cerebral malaria (table). In these children, in an endemic equatorial area and with a high level of immunity, parasite counts do not reliably predict the severity of P falciparum infection. Counts are not sufficient to guide treatment--especially the choice between the intravenous quinine required in cerebral malaria and oral therapy. Our results support the importance of a global clinical analysis of malaria infection, as reported by Rougemont et al. Hôpital Saint-Vincent-de-Paul,
DOMINIQUE GENDREL
75674 Paris, France
Faculty of Medicine,
MARYVONNE KOMBILA
Libreville, Gabon
Faculty of Medicine,
DOMINIQUE RICHARD-LENOBLE
Tours
D, Kombila M, Nardou M, Gendrel C, Djouba F, Richard-Lenoble D. Protection against Plasmodium falciparum infection in children with hemoglobin S. Pediatr Infect Dis J 1991, 10: 620-21 2 Philips RE, Solomon T Cerebral malaria in children. Lancet 1990; 336: 1355-60. 1. Gendrel
Chromosomal aberrations defining uveal melanoma of poor prognosis SIR,-Uveal melanoma is the most common primary intraocular malignancy. The estimated 15-year-survival rate after detection of the tumour is 46%.1 As in other malignancies, tumour size and cell type are major risk factors for metastasis. However, we do not know why the location of a uveal melanoma in the ciliary body is one of the most important factors for poor prognosis, even in statistical models with correction for all other risk factors.z°3 We propose that specific chromosomal aberrations explain the difference in survival rates for patients with choroidal or with ciliary-body melanomas. Cytogenetic analysis of uveal melanomas revealed monosomy of chromosome 3 and multiplication of chromosome 8q material as non-random chromosomal aberrations.4- These findings have been confirmed by DNA polymorphism studies.’ To date, 34 tumours with data about location are available (table). In uveal melanomas involving the ciliary body, chromosome 3 alleles were lost in 14 (70%) of 20 informative cases. Multiplication of chromosome 8q alleles was found in 14 (74%) of 19 informative cases. Only 2 of 20 informative cases did not have any of these aberrations. By contrast, of 13 choroidal melanomas, monosomy of chromosome 3 was seen in 3 (23%) and multiplication of chromosome 8q in 2 (15%). 10 tumours (77%) in this group did not have any of these aberrations. Differences in the frequency of these aberrations between uveal melanoma with ciliary-body involvement and choroidal melanoma are significant (p 0-011 for loss of chromosome 3 alleles, p = 0-002 for multiplication of 8q alleles; Fisher’s exact test). Thus, loss of chromosome 3 alleles and multiplication of 8q alleles may defme a subgroup of uveal melanoma with poor prognosis. =
692
CHROMOSOMES 3 AND 8 ABERRATIONS IN CILIARY BODY AND CHOROIDAL MELANOMA
TABLE I--ANALYSIS OF LINKAGE DISEQUILIBRIUM
__.
_
.
*p
