CD4 T cell count as predictor of Pneumocystis carinii pneumonia in children born to mothers infected with HIV

Statistical analysis

The proportion of children, by age, with a CD4 T cell count (either absolute number or as a percentage of total lymphocytes) below the threshold for prophylaxis was derived by the Kaplan-Meier method12 with follow up curtailed at the last CD4 T cell determination. For uninfected children a CD4 T cell count below the threshold after disappearance of transplacentally acquired antibody to HIV was ignored. For infected children CD4 T cell counts are relevant only if measured before the onset of P carinii pneumonia. The analysis, therefore, was restricted to children who had not yet developed P carinii pneumonia by using the conditional probability relationship: probability (CD4 <threshold (?) no P carinii pneumonia)= 1-[1-probability (CD4<threshold or P carinii pneumonia)]/probability (no P carinii pneumonia).

The analyses excluded 16 infected and 73 uninfected children who had not had a CD4 T cell determination in the first year of life.

Incidence of p carinii pneumonia

Between December 1984 and January 1993, 924 children were recruited from 10 centres. Of these, 111 children were infected with HIV, 571 were uninfected, and 242 had an indeterminate state of infection. P carinii pneumonia was diagnosed in 14 children (histologically confirmed in 11). The incidence of P carinii pneumonia was highest between 3 and 6 months of age (table 1). All children in whom the pneumonia had been diagnosed in the first year of life were aged between 2.9 and 6.2 months (table II). The cumulative incidence by 6 years of age was 16.0% (95% confidence interval 7.3% to 23.9%) in infected children and 2.0% (0.9% to 3.0%) in all children born to infected mothers. None of the children with P carinii pneumonia received antipneumocystis or antiretroviral treatment before diagnosis.

CD4 T Lymphocyte count as predictor for p carinii

Pneumonia

The following analysis was restricted to 11 of the 14 children for whom at east one CD4 T cell count was available before diagnosis of P carinii pneumonia. Figure 1 shows the CD4 T cell counts around the time of diagnosis for the children who developed P carinii pneumonia in the first year of life. Despite close monitoring, in which all children had lymphocyte phenotyping performed within two and a half months of diagnosis of P carinii pneumonia, only two children had counts which crossed the threshold for prophylaxis of 1500x10⁶ CD4 T cells/l before the pneumonia was diagnosed. Another two children had CD4 counts between 1500x10⁶ cells/l and 2000 x 10⁶ cells/l when last assessed 1.4 and 2.0 months before diagnosis of the pneumonia and, had the guidelines been adopted, their CD4 T cell counts would have been reassessed one month later, which could have triggered prophylaxis

Fig 1

CD4 cell counts around time of diagnosis of P carinii pneumonia for nine children in whom it developed in first year of life and who had CD4 T cell determination before diagnosis. Dotted line shows threshold for prophylaxis

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Of the two children who developed P carinii pneumonia after 1 year of age, one had a CD4 T cell count consistently below the threshold for prophylaxis (fig 2). The second child's CD4 T cell count fell sharply during the two months before diagnosis of the pneumonia, but the criteria for prophylaxis were not fulfilled. Distinct decreases in CD4 T cell count before diagnosis of pneumonia were also evident in many of the younger children (fig 1), although these are less obvious because of the narrow time scale.

FIG 2

CD4 T cell counts for two children who developed P carinii pneumonia (PCP) after first year of life. Dotted line shows threshold for prophylaxis.

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When the threshold CD4 T cell count was expressed as a percentage of total lymphocytes rather than an absolute number, no additional children were identified but one was missed. In summary, of the 11 children with CD4 T cell determinations predating diagnosis of P carinii pneumonia, only three clearly fulfilled the criteria for primary prophylaxis.

Age when children cross threshold for prophylaxis

Figure 3 shows, by state of infection, the proportion of children at each age who had not developed P carinii pneumonia but whose CD4 T cell count fell below the threshold for prophylaxis. Prophylaxis was indicated for 6% of infected children by 3 months of age, rising to 33% by 6 months and 62% by 12 months. A low CD4 T cell count was observed in 10% of uninfected children before the disappearance of maternal antibody to HIV. These analyses are sensitive to the frequency and ages at which lymphocyte determinations are performed. Under the slightly more intensive schedule recommended in the guidelines from the Centers for Disease Control even higher proportions of children would be anticipated to fulfil the criteria for prophylaxis. This was confirmed by simulation analyses which increased the estimate of the proportion of uninfected children who were eligible for prophylaxis to 18%.

FIG 3

Cumulative proportion of children by age with CD4 T cell count below threshold for prophylaxis for children infected with HIV who had not developed P carinii pneumonia and for uninfected children who were positive for antibody to HIV

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Guidelines from the centers for disease control

The sensitivity of the guidelines from the Centers for Disease Control may have been overestimated because of the retrospective nature of the data on which they are based. The threshold of 1500x10⁶ CD4 cells/l for children aged 1-11 months was based on the observation that 63 of 71 children diagnosed with P carinii pneumonia in the first year of life had a CD4 T cell count below this value.*RF 5,6,15-18* In most of these cases, however, lymphocyte phenotyping was performed at or after diagnosis, exaggerating the predictive value of CD4 T cell counts. In addition, since the infection with HIV of many of the children came to light only as a result of the episode of P carinii pneumonia delay between initial symptoms and diagnosis of the pneumonia may have been longer than for the closely monitored children in the European collaborative study. Moreover, a higher proportion of the children had other symptoms related to HIV infection before or concurrent with diagnosis of the pneumonia (possibly reflecting selective inclusion of symptomatic children in these series) than in the European collaborative study,^5,15 and immunological variables are more likely to be impaired in children with symptomatic than with asymptomatic HIV infection.19

In view of the apparent low sensitivity and specificity of the guidelines consideration could be given to their possible modification.3 One possibility would be to use clinical signs and symptoms instead of or as well as immunological markers. Prophylaxis is advisable for children with serious manifestations related to HIV infection, but we have shown that the absence of signs and symptoms does not preclude the possibility of P carinii pneumonia. Evidence of a rapid decline in CD4 T cell count around the time of onset of the pneumonia in some children points to a possible advantage in increasing the frequency of lymphocyte phenotyping. Indeed, a rapid decline in CD4 T cell count has been suggested as sufficient grounds for therapeutic intervention in adults,20 but large fluctuations of no immunological importance are common, particularly in children, because of large variability within people.^10,21 Although higher thresholds for prophylaxis would result in more children receiving treatment before they developed P carinii pneumonia, this would further decrease the specificity of the guidelines.

Alternative approach

An alternative approach would be to give prophylaxis to all children infected with HIV,^6,13 which would enable prophylaxis to be initiated before the period of highest risk for P carinii pneumonia. Routine early diagnosis of infection with HIV, however, is not yet practicable.22 Adequate protection for infected children would therefore necessitate giving treatment to all children born to infected mothers, including children who are uninfected, at least during the period of high risk for P carinii pneumonia. This would be difficult to justify since the cumulative incidence of this pneumonia by 6 years of age was only 2%.

Several factors need to be balanced against the benefit of delaying the progression of disease in children infected with HIV. These include the theoretical possibility of side effects resulting from early and prolonged treatment23; the cost of the drug and its delivery20; and the need to monitor children for CD4 T cell counts and adverse haematological reactions.3 It is also uncertain for how long prophylaxis should be given and whether it is as effective in preventing P carinii pneumonia in infants as it is in adults.24

Because of the low incidence of P carinii pneumonia no single study can provide a definitive analysis of the predictive value of CD4 T cell counts. It is important that data from other studies be examined to confirm our findings.

Collaborators in the European collaborative study are Dr C Giaquinto, Dr A De Rossi, Professor L Chieco-Bianchi, Professor F Zacchello (Universita degli Studi di Padova); Dr I Grosch-Worner, Dr M Vocks-Hauck, Dr M Langhof (Universitatsklinikum Rudolf Virchow, Berlin); Dr J Mok, Dr G Bird (City Hospital, Edinburgh); Dr F Omenaca Teres, Dr I Bates, Dr M C Garcia-Rodriguez (Hospital Infantil La Paz, Madrid); Dr C Canosa, Dr D M Galbis (Hospital La Fe, Valencia); Dr H Scherpbier, Dr G Mulder-Kampinga, Dr K Boer (Academisch Medisch Centrum, Amsterdam); Dr A B Bohlin, Dr E Belfrage (Huddinge and Danderyd Hospitals, Stockholm); Dr A Ferrazin, Dr C Gotta (Hospital San Martino, Genoa); Dr J Levy, Dr A Alimenti (Hospital St Pierre, Brussels); Dr A Mur, Dr H Yazbeck, Professor J Llorens (Hospital del Mar, Laboratorio Referencia de Cataluna, Barcelona).

We acknowledge the help we have had from Ms J Callis. We thank Dr R D'Elia, Dr A M Laverda, Dr E Ruga, Dr S Cozzani, Dr A Giacomelli, Dr A Pagliaro, Dr A Condini, Dr C Cattelan, Dr A Mazza, Professor B Grella, Dr A R Del Mistro, Dr A Amadori (Padua); Dr A Schafer, Dr B Zorr, Dr M Mielke, Professor U Wahn, Professor B Stuck, Dr J Woweries, Dr H Abdul-Khaliqu (Berlin); Dr R Hague, Dr F D Johnstone, Dr P L Yap, Dr S Burns, Dr J Inglis, Dr J Peutherer, Mrs S Rebus, Mrs F Mitchell, Mrs C Lockhart (Edinburgh); Dr G Fontan-Casariego, Dr R Martinez-Capico, Dr M D Jose, Dr M L Gonzalez, Dr M L Prieto (Madrid); Dr F Asensi, Dr M Otero, Dr D Perez Tamarit, Dr D Granda, Dr G Molina (Valencia); Dr C A B Boucher, Dr M Roos, the participants of the Dutch collaborative study of HIV infected women and their children (Amsterdam); Dr F Melica, Dr C Cirillo, Dr G Barigione, M Bellomo, F Caocci (Genoa); Dr S Sprecher, Prof N Clumeck (Brussels); and Dr E Gimenez, Dr C Sierra (Barcelona).

This study is a concerted action of the European Commission. The Medical Research Council provides support to the coordinating centre. Collaborating centres were supported by grants from the Ministero della Sanita-Istituto Superiore di Sanita, progetto AIDS 1989-1992 (Padua, Genoa); the Medical Research Council, the AIDS Virus Education Research Trust, the Scottish Office Home and Health Department (Edinburgh); Praeventiefonds number 28-1704 (Amsterdam); Bundesminister fur Gesundheit (Berlin); and Fonds de la Recherche Scientifique Medicale (Brussels).