Chronic lung disease in human immunodeficiency virus (HIV) infected children

The development of chronic lung disease is common in HIV-infected children. The spectrum of chronic HIV-associated lung disease includes lymphocytic interstitial pneumonia (LIP), chronic infections, immune reconstitution inflammatory syndrome (IRIS), bronchiectasis, malignancies, and interstitial pneumonitis. Chronic lung disease may result from recurrent or persistent pneumonia due to bacterial, mycobacterial, viral, fungal or mixed infections. In high tuberculosis (TB) prevalence areas, M. tuberculosis is an important cause of chronic respiratory illness. With increasing availability of highly active antiretroviral therapy (HAART) for children in developing countries, a rise in the incidence of IRIS due to mycobacterial or other infections is being reported. Diagnosis of chronic lung disease is based on chronic symptoms and persistent chest X-ray changes but definitive diagnosis can be difficult as clinical and radiological findings may be non-specific. Distinguishing LIP from miliary TB remains a difficult challenge in HIV-infected children living in high TB prevalence areas. Treatment includes therapy for specific infections, pulmonary clearance techniques, corticosteroids for children with LIP who are hypoxic or who have airway compression from tuberculous nodes and HAART. Children who are taking TB therapy and HAART need adjustments in their drug regimes to minimize drug interactions and ensure efficacy. Preventative strategies include immunization, chemoprophylaxis, and micronutrient supplementation. Early use of HAART may prevent the development of chronic lung disease.     

Hypercalcaemia complicating immune reconstitution in an HIV-infected patient with disseminated tuberculosis

An HIV positive man being treated for disseminated tuberculosis developed hypercalcaemia 17 days after starting highly active antiretroviral therapy (HAART). Hypercalcaemia resolved with stopping HAART and was thought to be due to immune reconstitution inflammatory syndrome.     

Acute respiratory failure following HAART introduction in patients treated for Pneumocystis carinii pneumonia.

Cases of paradoxical worsening of opportunistic infections shortly after the beginning of highly active antiretroviral therapy (HAART) prompted questions on the optimal timing of introduction of HAART in patients with inaugural AIDS-related opportunistic infections. We describe three cases of acute respiratory failure after early introduction of HAART in patients treated for Pneumocystis carinii pneumonia (PCP). The three patients had severe PCP that initially improved with anti-PCP and adjunctive steroid therapy. HAART was introduced 1 to 16 d after diagnosis of PCP, and steroids were stopped on Day 15. Seven to 17 d after HAART introduction, the three patients developed a second episode of severe acute respiratory failure with high-grade fever and patchy alveolar opacities on the chest roentgenogram. PCP resistant to cotrimoxazole, pulmonary superinfection, and drug-related pneumonitis were suspected but subsequently ruled out. Bronchoalveolar lavage and lung pathologic findings showed severe nonspecific pulmonary inflammatory foci surrounding a few persistent P. carinii cysts. All three patients recovered after HAART interruption or steroid reintroduction. We conclude that acute respiratory failure can recur after initiation of antiretroviral therapy in patients being treated for severe PCP. This phenomenon could result from rapid pulmonary recruitment of fully competent immune and inflammatory cells responding to a few persistent P. carinii cysts. A short course of steroid therapy may suppress this reaction.     

Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: a systematic review

HIV and tuberculosis (TB) are leading global causes of mortality and morbidity. Highly active antiretroviral therapy (HAART) is often initiated in patients being treated for TB. The immune recovery associated with HAART results in dramatic clinical benefits, but this restoration of immunity may result in immunopathological reactions. The immune reconstitution inflammatory syndrome can result in fever, nodal enlargement, and worsening pulmonary infiltrates observed on a chest radiograph, with or without recurrent respiratory symptoms. Several other manifestations have also been described. As a consequence, the use of HAART might not be appropriate during the first weeks of anti-TB therapy in HIV-infected patients. In this review, we summarize the incidence, clinical presentations, and potential mechanisms of these conditions and we describe therapeutic methods.     

Tuberculosis manifested by immune reconstitution inflammatory syndrome during HAART

The proportion of tuberculosis manifested by immune reconstitution inflammatory syndrome (IRIS) after HAART has not been established. We describe the incidence and clinical features of tuberculosis manifested by IRIS after HAART in an intermediate tuberculosis burden area. The findings suggest that a significant proportion of the tuberculosis occurring early after starting HAART is manifested by IRIS.     

Immune Reconstitution Inflammatory Syndrome (IRIS)—Another New Disease Entity Following Treatment Initiation of HIV Infection

After the introduction of highly active antiretroviral therapy (HAART) in 1995 it took 3 years to recognize the new syndrome of lipodystrophy as a long-term complication of HAART [1]. It was found to be a direct toxic consequence of the various drugs used in combination regimens. Another 2 years later, an additional syndrome was described in patients who recently initiated HAART—the immune reconstitution inflammatory syndrome (IRIS) [2–4]. Although already recognized in the pre-HIV era in patients with treatment for tuberculosis [5, 6) and leprosy [7), it became substantially more frequent in HIV-infected patients on HAART. The term IRIS describes a collection of different inflammatory disorders which are associated with paradoxical deterioration of various preexisting infectious processes following commencement of HAART in HIV-infected patients. These preexisting infections in individuals with IRIS may have been previously diagnosed and treated or may have been symptomless and later revealed by the patients improved capacity to mount an inflammatory response.     

Soft tissue abscess and lymphadenitis due to Mycobacterium avium complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy

Immune reconstitution inflammatory syndrome (IRIS) is an atypical and unexpected reaction related to highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infected patients. IRIS includes an atypical response to an opportunistic pathogen (generally Mycobacterium tuberculosis, Mycobacterium avium complex, cytomegalovirus and herpes varicella-zoster), in patients responding to HAART with a reduction of plasma viral load and evidence of immune restoration based on increase of CD4+ T-cell count. We reported a case of a patient with AIDS which, after a first failure of HAART, developed a subcutaneous abscess and supraclavicular lymphadenitis as an expression of IRIS due to Mycobacterium avium complex after starting a second scheme of HAART.     

Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era

OBJECTIVES: Highly active antiretroviral therapy (HAART) produces a rapid decline in plasma HIV-1 RNA levels with concomitant immune reconstitution. Probably due to the enhanced immune function, shortly after starting HAART, some latent opportunistic infections precipitated. The aim of this study was to illustrate the results of a survey on Cryptococcus associated mediastinitis occurring after HAART introduction, carried out at a referral centre of Infectious Diseases in the north-east of Italy, between October 1999 and October 2000. METHODS: All consecutive HIV-positive patients, naive to HIV-protease inhibitor therapy, and diagnosed with culture-proven cryptococcal infection were included in the study. Clinical and immuno-virological parameters before HAART and subsequently for 12 months were evaluated. RESULTS: Three of five patients were diagnosed with cryptococcal mediastinitis within a median time of 90 days (range, 60-150) after commencing HAART and fluconazole prophylaxis. Diagnosis was established by lymph node biopsy alone. Clinical improvement was documented when systemic anti-fungal therapy was combined with surgical drainage of the suppurative lesions. The role of immune restoration was confirmed by the significant increase in CD4 cell count, the reduction of HIV-RNA to undetectable levels and the prominent inflammatory reactions of lymph nodes. CONCLUSIONS: Our report suggests that HIV-positive patients with prior cryptococcal systemic infection may present a re-exacerbation of atypical cryptococcosis as a manifestation of immune restoration, even when fluconazole prophylaxis is ongoing.     

Immune reconstitution inflammatory syndrome associated with disseminated mycobacterial infection in patients with AIDS

Restoration of the immune system after highly active antiretroviral therapy (HAART) resulting from a quantitative and qualitative process of cell immune activity recovery may evolve with adverse clinical phenomena, known as the immune reconstitution inflammatory syndrome (IRIS). It can occur in association with several opportunist infections, although most reported cases have been related to mycobacterial infection caused by Mycobacterium tuberculosis and Mycobacterium avium. We describe three clinical cases of mycobacterial infection with different presentation patterns of IRIS after HAART. In each of these patients, immune reconstitution led to clinical manifestation of a latent infection, or clinical worsening of preexisting lesions, or manifestation of new lesions in the central nervous system. Clinical aspects of IRIS are presented in the paper and clinical management options for this event are carefully discussed.     

Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy

BACKGROUND: There is little systematic information regarding the immune reconstitution inflammatory syndrome (IRIS). OBJECTIVE: To determine the incidence, risk factors, and long-term outcome of IRIS in HIV-infected patients receiving highly active antiretroviral therapy (HAART) who were coinfected with one of three common opportunistic pathogens. DESIGN: A retrospective cohort identified through a city-wide prospective surveillance program. METHODS: A retrospective chart review was performed for 180 HIV-infected patients who received HAART and were coinfected with Mycobacterium tuberculosis, Mycobacterium avium complex, or Cryptococcus neoformans between 1997 and 2000. Medical records were reviewed for baseline demographics, receipt and type of HAART, response to antiretroviral therapy, development of IRIS, and long-term outcome. RESULTS: In this cohort, 31.7% of patients who received HAART developed IRIS. Patients with IRIS were more likely to have initiated HAART nearer to the time of diagnosis of their opportunistic infection (P < 0.001), to have been antiretroviral naive at time of diagnosis of their opportunistic infection (P < 0.001), and to have a more rapid initial fall in HIV-1 RNA level in response to HAART (P < 0.001). CONCLUSIONS: IRIS is common among HIV-infected persons coinfected with M. tuberculosis, M. avium complex, or C. neoformans. Antiretroviral drug-naive patients who start HAART in close proximity to the diagnosis of an opportunistic infection and have a rapid decline in HIV-1 RNA level should be monitored for development of this disorder.     

Immune restoration inflammatory syndromes: The dark side of successful antiretroviral treatment

The prevalence of cellular immunodeficiency has increased due to rising use of immunosuppressive therapies and the pandemic spread of HIV infection. More recently, the introduction of highly active antiretroviral therapy (HAART) in HIV has led to significant immune reconstitution, even in patients with previously long-lasting secondary immunodeficiency. HAART reduces morbidity and mortality in HIV infection and also changes the clinical course of prevalent subclinical opportunistic infections or autoimmune diseases. Atypical inflammatory disorders develop after initiation of HAART and have been summarized as “immune reconstitution syndrome,” “immune restoration disease,” and “immune restoration inflammatory syndrome.” However, diagnostic criteria and standards of therapy are yet to be defined. The awareness for these diseases is of increasing importance from a clinical point of view. This review summarizes the variety of immunoreconstitution disorders and describes possible diagnostic pitfalls. We also propose possible therapeutic options.     

针对结核/艾滋病双重感染病人实施抗病毒治疗的研究进展

针对结核/艾滋病（TB/HIV）双重感染病人的治疗极其复杂,并非是简单地将抗结核药物和抗病毒药物相加而成。由于药物的不良反应,免疫重构综合征的发生以及高死亡率等原因,TB/HIV双重感染的治疗在治疗方案和治疗时点上仍然没有明确的定论。截至目前,中国仍然无任何针对TB/HIV双重感染病人进行治疗的临床资料可借鉴。为此,文章对世界上各国针对TB/HIV双重感染治疗的研究进展进行综述。     

Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources.

Mycobacterium tuberculosis infection accounts for probably one third of human immunodeficiency virus (HIV) related immune reconstitution inflammatory syndrome (IRIS) events, particularly in developing countries where HIV and tuberculosis (TB) co-infection is very common. Small cohort studies of HIV-positive patients with active TB treated with antiretroviral therapy (ART) suggest an incidence of TB IRIS varying between 11% and 45%. Risk factors for TB IRIS that have been suggested in certain studies but not in others include: starting ART within 6 weeks of starting TB treatment; extra-pulmonary or disseminated disease; a low CD4+ lymphocyte count and a high viral load at the start of ART; and a good immunological and virological response during highly active antiretroviral therapy (HAART). It is important to agree on a clinical case definition of TB IRIS that could be used in resource-limited settings. Such a case definition could be used to determine the exact incidence and consequences of TB IRIS and would be valuable worldwide in clinical trials that are needed to answer questions on how this phenomenon could be prevented and treated.     

Infectious lung complications in patients with HIV/AIDS

PURPOSE OF REVIEW: The aim of this article is to review recent observations in the area of infectious lung complications in individuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Since the immunodeficiency was first characterized, it has been associated with enhanced susceptibility to opportunistic infection, and life-threatening infections of the lung in particular. In the past few years there have been a large number of reports documenting the changes to this disease profile in the age of highly active antiretroviral therapy (HAART). Furthermore, there have been considerable advances in our understanding of the immunology and vaccinology of many of the pathogens implicated in pulmonary infections in this context, including Mycobacterium tuberculosis, Streptococcus pneumoniae and Pneumocystis pneumonia. RECENT FINDINGS: In considering the time-course and spectrum of HIV-associated respiratory infections, the field must now be divided into studies undertaken in parts of the world where HAART is accessible and those where it is not. Despite the enormous impact of HAART, it has brought with it a new set of concerns, including the effects of immune restoration disease (IRD), and the complex interplay between HAART and tuberculosis therapy. SUMMARY: The overriding conclusion from recent experience is that HAART, in those parts of the world where it is readily available, has changed the clinical picture of infections associated with HIV, and needs to be available to patients across the developing world as well. Furthermore there have been important developments in vaccination programs against pathogens involved in HIV-associated pneumonia.     

Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome.

A 53-year-old man with acquired immunodeficiency syndrome (AIDS) developed clinical and radiological features compatible with sarcoidosis 14 months after starting highly active antiretroviral therapy (HAART). The CD4 lymphocyte count had increased from 5 cells/mm(3) to 235 cells/mm(3) with HAART. Transbronchial lung biopsy showed nonnecrotizing granulomas. All studies for an infectious etiology were negative. His condition improved after treatment with corticosteroids. To our knowledge, this is the fifth case report of sarcoidosis occurring after initiation of antiretroviral therapy for AIDS.     

Impact of highly active antiretroviral therapy on organ-specific manifestations of HIV-1 infection

In the last 10 years, interesting results have been reported concerning the impact of highly active antiretroviral therapy (HAART) on the changing pattern of organ-specific manifestations of HIV-1 infection. There has been a clear step-wise reduction in the incidence of several opportunistic infections (OIs), particularly Pneumocystis carinii pneumonia, whereas a nonsignificant reduction in incidence has been observed for other organ-specific diseases, including invasive cervical cancer and Hodgkin disease. In addition, several organ-specific manifestations, including HIV-associated nephropathy, wasting syndrome and cardiomyopathy, are a direct consequence of damage by HIV-1, and so HAART may have a therapeutic effect in improving or preventing these manifestations. Finally, the introduction of HAART has seen the emergence of several complications, termed immune reconstitution inflammatory syndrome, which includes OIs such as cytomegalovirus vitritis, Mycobacterium avium complex lymphadenitis, paradoxical responses to treatment for tuberculosis, and exacerbation of cryptococcosis. Because not all HIV-1 organ-specific manifestations are decreasing in the HAART era, this review will analyse the influence of HAART on several organ-specific manifestations, and in particular OIs related to several organs, cerebral disorders and HIV-1-related neoplasia.     

Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART

OBJECTIVE: Recent epidemiological studies in adults suggest that HAART can prevent the development of tuberculosis in HIV-infected individuals, but the mechanisms are incompletely understood and no data exist in children. We investigated whether changes in mycobacterial-specific immune responses can be demonstrated in children after commencing antiretroviral therapy. DESIGN: We measured mycobacterial growth in vitro using a novel whole-blood assay employing reporter-gene tagged bacillus Calmette-Guérin (BCG) in a prospective cohort study in the tuberculosis-endemic environment of South Africa. Key cytokines were measured in supernatants collected from the whole-blood assay using cytometric bead array. PATIENTS: A cohort of 15 BCG-vaccinated HIV-infected children was evaluated prospectively for in-vitro antimycobacterial immune responses before and during the first year of HAART. All children had advanced HIV disease. Nine children completed all study timepoints. RESULTS: Before HAART, blood from children showed limited ability to restrict the growth of mycobacteria in the functional whole-blood assay. The introduction of HAART was followed by rapid and sustained reconstitution of specific antimycobacterial immune responses, measured as the decreased growth of mycobacteria. IFN-gamma levels in culture supernatants did not reflect this response; however, a decline in TNF-alpha was observed. CONCLUSION: This is the first study using a functional in-vitro assay to assess the effect of HAART on immune responses to mycobacteria in HIV-infected children. Our in-vitro data mirror the in-vivo observation of decreased susceptibility to tuberculosis in HIV-infected adults receiving antiretroviral agents. This model may be useful for further characterizing immune reconstitution after HAART.     

Use of rifabutin with protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis.

Drug interactions between rifamycins and highly active antiretroviral therapy (HAART) have raised concerns in the treatment of human immunodeficiency virus (HIV)-infected patients with tuberculosis. We conducted a study of this interaction by measuring serum drug levels of all HIV-infected patients with tuberculosis who were admitted to A. G. Holley State Tuberculosis Hospital (Florida) from October 1997 through December 1998, who were concomitantly treated with rifabutin and HAART. All 25 patients studied became culture-negative within 2 months of initiation of therapy for tuberculosis and remained negative for a median of 13 months follow-up after completion of therapy. HIV viral loads (mean+/-SEM) decreased significantly from 4.95+/-0.21 log10 copies/mL before initiation of HAART to 2.77+/-0.07 log10 copies/mL before discharge (P<.001); 20 of 25 patients achieved viral loads of <500copies/mL. In summary, the concomitant use of rifabutin and HAART can lead to successful treatment of HIV-infected patients with tuberculosis without increased side effects.     

Tuberculosis in HIV-infected persons in the context of wide availability of highly active antiretroviral therapy.

Highly active antiretroviral therapy (HAART) greatly reduces the risk of developing tuberculosis for HIV-infected persons. Nonetheless, HIV-associated tuberculosis continues to occur in countries where HAART is widely used. To identify the characteristics of HIV-infected persons who develop tuberculosis in the context of the availability of HAART, the current authors analysed data taken from 271 patients diagnosed, in Italy, during 1999-2000. These patients represent 0.7% of the 40,413 HIV-infected patients cared for in the clinical units participating in this current study. From the data it was observed that 20 patients (7.4%) had a previous episode of tuberculosis whose treatment was not completed. Eighty-one patients (29.9%) were diagnosed with HIV at tuberculosis diagnosis, 108 (39.8%) were aware of their HIV status but were not on antiretroviral treatment and 82 (30.3%) were on antiretroviral treatment. Patients on antiretroviral treatment were significantly less immunosuppressed than patients with HIV diagnosed concurrently with tuberculosis, or other patients not on antiretrovirals (median CD4 lymphocytes count: 220 cells x mm(-3) versus 100 cells x mm(-3), and 109 cells x mm(-3), respectively). No significant differences in clinical presentation of tuberculosis according to antiretroviral therapy status were recorded. Failure of tuberculosis control interventions (e.g. noncompletion of treatment) and of HIV care (delayed diagnosis of HIV infection and suboptimal uptake of therapy) may contribute to continuing occurrence of HIV-associated tuberculosis in a country where highly active antiretroviral therapy is largely available. However, a significant proportion of cases occur in patients who are on antiretroviral treatment.     

Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals

Immune reconstitution disease (IRD) in HIV-infected patients is an adverse consequence of the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral treatment (HAART). Previously subclinical infections are "unmasked" or pre-existing opportunistic infections clinically deteriorate as host immunopathological inflammatory responses are "switched on". IRD is most frequently associated with mycobacterial infections. Our literature search identified 166 published cases of IRD associated with mycobacterial infections. We review the underlying immunological mechanisms, difficulties surrounding case definition and diagnosis, the wide diversity of clinical manifestations, and treatment. The importance of screening patients for mycobacterial disease before starting HAART and the critical impact of the timing of commencement of HAART in patients receiving treatment for tuberculosis are highlighted. We also discuss the problem of IRD associated with mycobacterial diseases in developing countries where tuberculosis prevalence is high and access to HAART is currently expanding.