Immunosuppression and fungal risk among individuals living with HIV

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“An outbreak of community-aquired Pneumocystis carinii pneumonia: Initial manifestation of cellular immune dysfunction”

The Morbidity and Mortality Report (MMWR) reported the first cases of what would become the HIV pandemic in June 1981: 5 previously healthy homosexual men (MSM) in Los Angeles were found to have biopsy-confirmed Pneumocystis jirovecii pneumonia as well as confirmed CMV disease or virus shedding within 5 months of the diagnosis of Pneumocystis pneumonia and candida mucosal infections (Centers for Disease Control (CDC), 1981a). This report in the MMWR alerted the medical and public health communities 4 months before the first peer-reviewed article was published (Hymes et al., 1981). Scientists in the Parasitic Diseases division of CDC’s Center for Infectious Diseases were already concerned with an increase in requests for pentamidine isethionate to treat unusual cases of PCP in New York. One month later, a new MMWR report included 26 cases of Kaposi’s sarcoma in young male homosexuals, 20 in New York and 6 in San Francisco, 7 of whom also had PCP, CMV or other opportunistic infections (OI) (Centers for Disease Control (CDC), 1981b). In July 1981, another 10 cases of PCP (without Kaposi’s sarcoma) were identified. The CDC then formed a task force on Kaposi’s sarcoma and opportunistic infections. Results from active surveillance in the United States rapidly established that the syndrome was new, and showed that the number of cases was increasing rapidly (“Epidemiologic aspects of the current outbreak of Kaposi’s sarcoma and opportunistic infections,” 1982). In England, the first case of PCP and acquired cellular immunodepression was reported in 1981 in a MSM with PCP who had been to the USA (du Bois et al., 1981). In France, the first reported case was that of a MSM who was admitted to hospital in 1981 with PCP (Rozenbaum et al., 1982). The name “acquired immunodeficiency syndrome” (AIDS) was first used in 1982. By the end of 1982, the case distribution strongly suggested that AIDS was caused by an agent transmitted through sexual contact between men (Centers for Disease Control (CDC), 1982a; Jaffe et al., 1983) and between men and women (Centers for Disease Control (CDC), 1983a; Harris et al., 1983), and also through blood exposure among injecting-drug users and recipients of blood or blood products (Centers for Disease Control (CDC), 1982b, 1982c, 1982d). Cases were also identified among infants born to women with AIDS or at risk of AIDS (Centers for Disease Control (CDC), 1982e), and persistent unexplained lymphadenopathy emerged as a frequent feature (Centers for Disease Control (CDC), 1982f). To prevent transmission of AIDS, in 1983 the USA Public Health Service used epidemiological information about the condition to recommend that sexual contact be avoided with persons known or suspected to have AIDS, and that persons at increased risk for AIDS refrain from donating plasma or blood (Centers for Disease Control (CDC), 1983b, 1982d). Work was intensified toward developing safer blood products for persons with hemophilia. These recommendations were developed and published only 21 months after the first cases had been reported and before the first published report by F Barre-Sinoussi and Luc Montagnier’s team identifying the causative retrovirus (Barré-Sinoussi et al., 1983). By 1984, the National Heart, Lung, and Blood Institute (NHLBI) had analyzed the types and frequencies of pulmonary diseases in 441 patients with AIDS and found that 373 (85%) had PCP (27). In 1986, the French and Americans agreed to call this retrovirus HIV. By the end of 1986, 38 401 cases of AIDS had been identified by WHO: 31 741 in the USA, 3858 in Europe, 2323 in Africa, 395 in Oceania, and 395 in Asia.

PCP: epidemiological changes

During the early years of the AIDS pandemic, PCP accounted for 2/3 of AIDS-defining illnesses in patients in the USA, and an estimated 75% of HIV-infected individuals developed PCP during their lifetime (Hay et al., 1988; Morris et al., 2004). Rates of PCP were as high as 20/100 PY among those with CD4 <200/mm3. The first decline in the incidence of PCP occurred after the introduction of anti-Pneumocystis prophylaxis in 1989 (Jones et al., 1999). The advent of cART resulted in further declines in PCP and other opportunistic infections (figure 1). Many studies showed a dramatic fall in the incidence of AIDS-defining clinical illness (ADI) and improved survival (Palella et al., 1998). In Europe, the Euro SIDA study (Mocroft et al., 2000; Weverling et al., 1999) showed a reduction in the incidence of PCP from 4.9 cases/100 PY before March 1995 to 0.3 cases/100 PY after March 1998. Yet PCP remains one of the most common AIDS-defining illnesses in resource-rich settings and was the second most frequent ADI in France in 2001-2003 (Grabar et al., 2008; Kaplan et al., 2000; Morris et al., 2004). One large prospective study showed that PCP survival at 3 years rose from 51% in the pre-cART era to 87% in 2001-2003 (Grabar et al., 2008). Another study in France showed that PCP was the second invasive fungal disease, and while PCP’s incidence decreased in HIV infected individuals, PCP’s incidence increased in HIV-seronegative patients between 2001 and 2010 (Bitar et al., 2014).

Paracoccidioi domycosis

Paracoccidio idomycosis is not commonly reported in AIDS patients, for unexplained reasons. All reported cases of AIDS-associated paracoccidioidomycosis have occurred in Brazil, apart from one case reported in Venezuela. Most patients had disseminated disease, with advanced AIDS and CD4 cell counts well below 200/L.
Diagnosis of paracoccidioidomycosis is usually based on direct microscopic examination and culture of clinical specimens, most commonly skin and lymph nodes. Culture of blood, bone marrow, and sputum may also be positive. Tests for P. brasiliensis antigen and PCR for P. brasiliensis DNA are promising new diagnostic tools.
First-line therapeutic options include trimethoprim-sulfamethoxazole, amphotericin B, ketoconazole, and itraconazole. Lifelong maintenance therapy with trimethoprim-sulfamethoxazole or itraconazole is recommended (Paniago et al., 2005).

Other opportunistic moulds: aspergillosis

Invasive aspergillosis has been reported among patients with advanced HIV disease, especially those with CD4 cell counts <50/ml (Denning et al., 1991; Khoo and Denning, 1994; Lortholary et al., 1993). The classical risk factors for invasive aspergillosis, namely neutropenia and corticosteroid therapy, were absent in many AIDS patients with Aspergillus infection. The lungs are the most common site of infection. In a study of 33 AIDS patients with invasive aspergillosis, most of whom had pulmonary disease, the predominant symptoms were fever, cough and dyspnea, while chest pain and hemoptysis were less frequent (Lortholary et al., 1993). Chest radiographs often show nodular lesions and cavitary infiltrates suggestive of aspergillosis. Bilateral interstitial infiltrates are also noted. Invasive necrotizing tracheobronchitis, manifested by acute dyspnea and wheezing, is a clinical form of aspergillosis also seen in AIDS patients. Bronchoscopy reveals necrotic ulceration of the trachea, with pseudomembranes (Kemper et al., 1993). Obstructing bronchial aspergillosis with chest pain, hemoptysis and dyspnea may precede the onset of necrotizing tracheobronchitis (Denning et al., 1991). The majority of patients have a prior history of pulmonary infection. Preexisting cystic pulmonary lesions and bullae may be risk factors for invasive pulmonary aspergillosis in patients with AIDS. Disseminated aspergillosis often involves the CNS and myocardium. Aspergillus endocarditis and sinusitis have also been reported among patients with AIDS.
There is a good correlation between Aspergillus-positive bronchoalveolar lavage fluid culture and histologically proven aspergillosis in immunocompromised patients, including AIDS patients. The Aspergillus species most often implicated are fumigatus, flavus, niger and terreus. Detection of galactomannan antigen in serum or bronchoalveolar lavage fluid, and/or Aspergillus PCR, may help to establish the diagnosis of invasive disease.
Although not specifically studied in AIDS patients, voriconazole has now become the recommended therapy for invasive aspergillosis in all patient groups (Walsh et al., 2008). Interactions with protease inhibitors and non-nucleoside reverse transcriptase inhibitors must be carefully monitored when azole agents are used. An alternative therapy is a lipid formulation of amphotericin B. The prognosis of invasive aspergillosis in AIDS patients is poor, with a mean survival time of only 2–4 months despite antifungal treatment. This opportunistic infection is very unusual among patients on effective cART.


Immunosuppression and fungal risk among individuals living with HIV

The earliest reports of AIDS showed that profound depletion of circulating CD4 T cells was central to the immune deficiency that defined the syndrome (Gottlieb et al., 1981; Masur et al., 1981). The same investigators also recognized that, despite the profound immune deficiency, activation of T cells (Gottlieb et al., 1981) and B cells (Lane et al., 1983) was also characteristic of this syndrome. The pathology of HIV disease is complex and multifaceted. In addition to high levels of systemic viral replication, HIV infection results in chronic immune activation and overall immunological dysfunction, which are closely associated with progression to AIDS.
Alteration of mucosal tissue:
HIV directly infects and depletes CD4 cells. The depletion occurs first in mucosal tissues, where large numbers of activated memory T cells expressing CCR5 chemokine receptors are present. As the majority of T cells reside within mucosal tissues, early loss of memory T cells leads to the loss of most of the body’s T cells (Brenchley and Douek, 2008). Around 90% of gut-associated lymphoid tissue (GALT) T cells are depleted within 2 weeks of simian immunodeficiency virus acquisition (Mattapallil et al., 2005). During acute HIV infection, the viral RNA is detectable in 0.01-1% of peripheral T cells, compared to 60% of mucosal memory CD4 T cells (Brenchley et al., 2004; Mattapallil et al., 2005). Slower depletion of CD4 T cells in peripheral tissues and blood ensues (Douek et al., 2003). While cART can in most cases restore immunity, reflected by CD4 cell recovery, T cells in the gastrointestinal tract usually fail to recover. HIV infection damages the tight epithelial barrier of the gastrointestinal tract, leading to microbial translocation, severe immunological dysfunction and chronic immune activation (Brenchley et al., 2006; Brenchley and Douek, 2008; Mehandru et al., 2006; Tincati et al., 2009).
Altered functionality and turn-over of CD8 T cells, B cells and innate immune cells are also observed (Paiardini et al., 2004; Ribeiro et al., 2002). Altered B cell function affects antibody production (Moir and Fauci, 2009), while altered NK cell function reduces cytokine production and increases cytotoxicity (Alter et al., 2004; Reeves et al., 2010). Dendritic cells and macrophages are also dysfunctional (Estes et al., 2010; Wallet et al., 2010).
Among CD4 and CD8 T cells, HIV infection leads to a loss of essential naïve and central memory cell populations, resulting in an increased frequency of short-lived effector cells (Klatt et al., 2013). T cell maturation is also affected, with low numbers of circulating naïve CD4 and CD8 T cells (Lederman et al., 2011). Zeng et al explained how, in secondary lymphoid tissue, immune activation leads to fibrosis and architectural distortion of the fibroblast reticular network, limiting access to IL-7 (Zeng et al., 2012). This fibrosis and decreased access to IL-7 would deplete naïve T cells and limit immune reconstitution, as shown in the figure below.

Table of contents :

Chapter 1. State of the art: fungal infections in individuals living with HIV
a) PCP and the discovery of the HIV/AIDS pandemic
i) “An outbreak of community-acquired Pneumocystis carinii pneumonia: Initial manifestation of cellular immune dysfunction”
ii) PCP: characteristics
iii) PCP: trends over time
b) Other fungal infections in HIV-infected individuals
i) Cryptococcosis
ii) Dimorphic fungi
(1) Histoplasmosis
(2) Coccidioidomycosis
(3) Penicilliosis
(4) Other dimorphic fungi
iii) Other opportunistic moulds: aspergillosis
c) Immunosuppression and fungal risk among individuals living with HIV
i) Immunosuppression among individuals living with HIV
ii) Immune regulation and fungi
(1) CD4+ lymphocyte defects
(2) Other defects
(3) Immunosuppression and invasive aspergillosis
ii) Impact of cART on fungal infections
Chapter 2. Methods
1) The French Hospital DataBase On HIV; ANRS CO4 Cohort
a) Creation of the FHDH – ANRS CO4 cohort (FHDH)
b) Objectives
c) Data collected
d) Published results from FHDH
2) Study of Pneumocystis jirovecii pneumonia (PCP) in the FHDH
a) Definition of cases
b) Selection of patients
3) Study of invasive aspergillosis (IA) in the FHDH
a) Selection of patients
b) Data collection: national retrieval of medical records
c) Validation of IA cases
4) Statistical methods
a) Estimation of prevalence and incidence in the FHDH
i) PCP
ii) Invasive aspergillosis (IA)
b) Survival estimates for PCP and invasive aspergillosis
i) PCP
ii) Invasive aspergillosis
c) Study of risk factors using Cox proportional hazards models
i) PCP
ii) Invasive aspergillosis (IA)
Chapter 3. Trends in PCP among HIV-infected individuals in France in the cART era
Article 1. Critical importance of long-term adherence to care in HIV infected patients in the cART era: new insights from Pneumocystis jirovecii pneumonia cases over 2004-2011 in the FHDH-ANRS CO4 cohort.
Denis B, Guiguet M, de Castro N, Mechaï F, Revest M, Mahamat A, Gregoire GM, Lortholary O, Costagliola D, PLoS One. 2014 Apr 11;9(4):e94183. doi: 10.1371/journal.pone.0094183. eCollection 2014.
Chapter 4. Invasive aspergillosis in HIV-infected individuals and survival trends over a 20-year period in France
Article 2. Relevance of EORTC Criteria for the Diagnosis of Invasive Aspergillosis in HIVInfected Patients, and Survival Trends Over a 20-Year Period in France.
Denis B, Guiguet M, de Castro N, Mechaï F, Revest M, Melica G, Costagliola D, Lortholary O; French Hospital Database on HIV Agence Nationale de Recherche sur le SIDA et les hépatites virales, France CO4. Clin Infect Dis. 2015 Oct 15;61(8):1273-80
Chapter 5. Discussion and perspectives


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