Three to seven concurrent AIDS-defining disorders at first hospitalization of AIDS presenters as an unexpected emerging feature during the era of highly active antiretroviral therapy

Although the introduction of potent highly active antiretrovirial therapy (HAART) has significantly changed the natural history of HIV disease in industrialized countries since 1996 [1–4], this feature does not apply to patients with either a delayed or a missed diagnosis of HIV infection or voluntarily neglected HIV disease [5,6]. Such patients remain at high risk of developing an advanced stage illness, characterized by multiple AIDS-defining disorders, and which is recognized only at their first hospitalization. Five out of 10 cases of AIDS detected and notified during the first 4 months of 2002 at our reference centre in northern Italy were patients whose HIV infection was either missed or neglected. This situation led to the recognition of advanced AIDS at the first hospital admission of all these patients, when three to seven concomitant AIDS-related diseases were diagnosed concurrently. A 59-year-old heterosexual men with unknown HIV infection was admitted suffering from Pneumocystis carinii and Staphylococcus aureus pneumonia, Candida albicans and Cryptococcus neoformans septicaemia, oesophageal candidiasis, disseminated multiresistant Mycobacterium kansasii infection, and severe wasting syndrome, when his CD4 lymphocyte count was 44 cells/μl, and viraemia was more than 500 000 HIV-RNA copies/ml. In a 19-month-old adopted African child, HIV infection was discovered concurrently with P. carinii disease, recurrent bacterial pneumonia, and systemic cytomegalovirosis, which occurred when viraemia was greater than 500 000 copies/ml, and the CD4 lymphocyte count was limited to 187 cells/μl. A 36-year-old woman recently immigrated from Morocco had her HIV disease diagnosed concurrently with P. carinii pneumonia, Candida esophagitis, and advanced cachexia: laboratory examination at presentation included a CD4 cell count of 12 cells/μl, and a viral load of 110 000 copies/ml. A 38-year-old intravenous drug addict had HIV infection detected in 1990, but denied further examinations and treatments, and was hospitalized for the first time when P. carinii, Alcaligenes xylosoxidans, Stenotrophomonas maltophilia and S. aureus pneumonia was detected, concurrently with disseminated cytomegalovirosis, neurotoxoplasmosis, severe wasting syndrome, neutropenia, and hepatitis C virus co-infection. His baseline CD4 cell count was 4 cells/μl, whereas viraemia accounted for 340 000 HIV-RNA copies/ml. Finally, a 50-year-old ex-intravenous drug user had never undergone clinical or laboratory examinations from the early detection of HIV disease in 1986, until P. carinii pneumonia, group B Salmonella sepsis, wasting syndrome, a Salmonella liver abscess, and chronic hepatitis C virus, became concomitantly evident: upon admission; a CD4 cell count of 37 cells/μl and viraemia of 80 000 HIV-RNA copies/ml were found. All our five late AIDS presenters received appropriate antimicrobial and supportive therapy, together with HAART, and obtained a slow cure or amelioration of their multiple AIDS-related disorders, together with a 60–500% increase in the CD4 lymphocyte count, and a 1.5–3.5 log10 decrease in HIV-RNA levels 3 months after hospitalization, compared with baseline levels. Multiple, concurrent AIDS-defining diseases have been anecdotally described to date as single case reports or small series, usually focusing on diagnostic difficulties. In 1993, Reed et al. [7] underlined that multiple concomitant opportunistic diseases are a rare event in the setting of HIV infection, but they may be underestimated when clinical suspicion is lowered by the first obtained diagnosis, especially when the signs and symptoms of more than one disorder overlap [2,3,7]. As a consequence, several diagnoses missed during life were detected only by necropsy findings [8]. Despite the availability of potent combination antiretroviral therapy, which also remains effective in end-stage HIV disease [1,2,4], the frequency of individuals presenting with AIDS seems to show a progressive increase during the HAART era, because the great majority of these patients cannot take real advantage of all the present diagnostic and therapeutic resources for the correct management of HIV infection [6]. In the meantime, although the quantitative and functional recovery of the immune system prompted by HAART is expected to reduce significantly the incidence of opportunistic infections (especially those related to a very low CD4 lymphocyte count), it is not the same for some AIDS-related neoplasms, such as lymphoma [1,2,9]. In our 1984–2001 single-centre experience based on 722 notified cases of AIDS, a double or triple AIDS-defining illness was concurrently discovered in only 27 and three cases (3.7 and 0.4%), respectively, so that the 50% rate of patients diagnosed with AIDS with three to seven concurrent AIDS-related disorders looks extremely surprising, and seems to deserve careful attention, in order to plan adequate preventative, public health, and therapeutic strategies. To the best of our knowledge, literature reports referring to three or more concomitant defining diseases at the time of the first AIDS diagnosis are virtually absent, after careful and extensive search performed through electronic databases, such as Medline and Current Contents. In particular, a double haematogenous Candida–Cryptococcus co-infection appears to be a very exceptional event, never reported before even in immunocompromised individuals other than AIDS patients. Moreover, although in the pre-HAART era, long-term underlying deep immunodeficiency prompted a number of relapses of opportunistic infections or novel AIDS-related diseases in the period ranging from AIDS diagnosis to terminal illness and death, the concurrent disclosure of more than one or two AIDS-defining events proved very infrequent [1,4]. The extensive introduction of HAART was expected to reduce further these occurrences during the past few years [1–4], but our data seem to point to a worrying opposite tendency, which seems attributable to epidemiological rather than clinical or therapeutic issues. Therefore, the availability of very potent and varied anti-HIV therapeutic strategies paradoxically does not match with the persisting diagnosis of advanced cases of HIV disease, which continue to occur in patients who were unaware of their infection, were denied HAART, or had insufficient adherence levels to prescribed antiretroviral therapy or antimicrobial prophylaxis [5,6]. Unfortunately, the numerous information programmes implemented so far in advanced countries also do not appear to be sufficient to contain the spread of the HIV epidemic, and to obtain the early recognition and effective and timely treatment of all patients with HIV infection (including those with missed or neglected diagnoses). Further preventative and educational efforts are needed for special population targets (i.e. the elderly, present or former intravenous drug addicts, immigrants, minorities, children exposed to vertical HIV infection, individuals who may be unaware or voluntarily underestimated the risk and evolution of their HIV infection, and their partners) [10], because all these individuals remain at risk of acquiring HIV infection, suffer from delayed recognition, and have an increased risk of advanced, potentially life-threatening HIV disease, including multiple concurrent AIDS-related disorders, never seen even before the introduction of HAART.