The decision as to when to start anti-retroviral therapy is made even more difficult when CD4 cell counts are not available . Antiretroviral therapy (ART), which is free at the point of delivery, has been available in Malawi since July 2004. Eligibility for ART in HIV-infected patients is defined either by a CD4 cell count of less than 200 cells/μl or a clinical diagnosis of WHO stage 3 or 4 disease. Resource limitations in Malawi preclude the use of CD4 cell counts in the vast majority of patients and therefore the decision to start ART is made on clinical grounds. This strategy has the disadvantage that many patients start ART too late to gain optimal benefit from the treatment. Until CD4 cell count testing becomes universally accessible , there is an urgent need to identify cheap, non-invasive markers of disease progression to assist in the identification of patients with advanced but asymptomatic HIV disease. The occurrence of grey nails in some ART-naive HIV-positive African patients is striking (Fig. 1) and relatively easy to identify . This sign has not previously been correlated with stage of HIV disease. We investigated the relationship between grey nails and CD4 cell count to determine whether this sign might identify patients likely to benefit from ART.
Adults admitted to the Queen Elizabeth Central Hospital, Malawi, were recruited with informed written consent. In-patients with abnormal nails were recruited together with a patient in a neighbouring bed with normal nails. Outpatients were recruited in an unselected sequential manner once weekly over the same period. All participating patients were asked to consent to HIV and CD4 cell count testing after appropriate pre-test counselling. Patients' hands were photographed using bright indoor daylight and details regarding current health and medication recorded. The study protocol was approved by the local research ethics committee.
All photographs were viewed on two separate occasions by three independent observers who were blinded to patient identity, HIV status and CD4 cell count. Nail pigmentation was scored as pink, grey, distal banded or indeterminate (Fig. 1). Distal banding refers to a transverse band of darker than normal nail pigmentation, 1 to 3 mm in width, in the distal nail bed. Examples of indeterminate nail pigmentation include poor photographic representation, fungal nail disease and instances where the nails were considered to have abnormal pigmentation but which did not fit into the categories of either grey or distal banding. Where an individual observer's responses for the same picture were discrepant, they were asked to look at the picture again in order to force a decision where possible. Patients who declined HIV testing, who did not have a CD4 cell count, or in whom their medical condition or medication might alter nail colour were excluded (e.g. cyanosis, antiretroviral or other drugs known to caused changes in nail pigmentation).
A total of 107 in-patients (13% of admissions) were recruited to the study in a case–control manner and 135 outpatients were recruited over the same 6-week period. Twenty subjects were excluded due to concurrent medication (n = 9), missing data (n = 5) or lack of consent to HIV testing (n = 6). The recruited group had mean age of 34.2 years (SD, 9.7 years); 134 of 222 (60%) were male and 159 of 222 (72%) of the subjects were HIV infected.
Grey or ‘distal banded’ (DB) nails were recorded in 53, 63 and 55 of these cases by the three independent observers respectively (κ = 0.66; P < 0.0001) . Four HIV-negative patients were identified by all three observers as having either grey or DB nails. When compared with pink nails, ‘grey or DB nails’ was strongly associated with a CD4 cell count of less than 200 cells/μl (chi-squared P =0.0001 for observers 1 and 2 and P = 0.012 for observer 3).
The positive predictive values of grey or DB nails for a CD4 cell count of < 350 and < 200 cells/μl were 92 and 81%, respectively. Specificity at these two cut off points was 87 and 85%, and sensitivities were 45 and 56%. Of the 53 patients with grey or DB nails, 21 did not meet clinical criteria for ART and 16 (76%) of these had a CD4 cell count of less than 200 cells/μl.
Grey nails have been associated with HIV infection  but we have shown significant correlation of this sign with a low CD4 cell count. The specificity of this sign compared favourably with other WHO stage III diagnoses such as oral candida . The sensitivity was low, as is the case with all clinical markers of HIV progression. In the present study 75% of HIV-infected individuals with grey nails had a low CD4 cell count but were denied ART using current clinical criteria. For clinicians working in sub-Saharan Africa without access to CD4 count testing, grey or DB nails represent an additional staging sign to help identify a sub-group of patients likely to benefit from ART.
We gratefully acknowledge the help of Dr Joep van Oosterhout, Dr Clare Scarborough, Dr David Lalloo and Dr Sarah White for diagnostic opinion on photographs, advice on funding and study design and for advice on statistical analysis.
Sponsorship: Laboratory costs were paid through the Jean Clayton Fellowship, Liverpool School of Tropical Medicine. M.S. is supported by a grant from the Meningitis Research Foundation. S.G. and N.F. hold Career Development Fellowships from the Wellcome Trust (UK). The funding sources had no involvement in the design, data collection, analysis, writing or decision to submit for publication.
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