Epidemiology and transmission

Pneumocystis carinii is ubiquitous and apparently encountered by the population in many geographical areas without disease manifestation (Pifer et al. 1978; Smulian et al. 1993). Most humans appear to be exposed to Pneumocystis within 2 years after birth (Hong 1991). An increased rate of seropositivity is seen with age (Meuwissen and Leeuwenberg 1972; Meuwissen et al. 1973) in children in Europe, the US, and Gambia.

Despite the global presence of the organism, geographical differences are seen in prevalence of PCP. PCP is more frequently detected in northern Europe and the US as compared with southern Europe, Africa, and Asia (Lucas et al. 1988; Elvin et al. 1989). Several factors may account for this difference. It has been attributed to the fact that under conditions of crowding and poor hygiene, other pathogens, such as Mycobacterium tuberculosis in the environment of immunosuppressed individuals, will cause severe and even fatal disease within a short time, so that Pneumocystis would be masked or not have sufficient time to establish itself. The clinical profile of Indian patients with HIV bears much resemblance to those seen in African countries owing perhaps to the similar background of poverty, malnutrition, and spectrum of endemic infection (Giri et al. 1995). However, differences in virulence or degree of exposure cannot be ruled out as contributing factors explaining the observed geographical differences (Chaisson and Moore 1997). The fact that PCP is less common in African HIV patients living in Europe (Biggar 1986) does not exclude the possibility that there are genetic differences in susceptibility between hosts.

In part, the geographic differences may be explained by the difference in diagnostic capacity between these regions. Indirect evidence for P. carinii being prevalent in Gambia is provided by serological data which indicate a high prevalence of P. carinii (Wakefield et al. 1990).

More than 80% of the reported PCP cases are homo- and bisexual men and injection drug users. The remaining cases are hemophiliacs, persons who get infected by heterosexual contacts, blood transfusion recipients, and children infected pre- or perinatally (Bunikowski et al. 1992). The pathophysiology of HIV infection is incompletely understood, but is in large part related to the destruction of helper CD4 lymphocytes. This results in immune dysfunction and the development of a variety of opportunistic infections.

Significant differences in CD4 lymphocyte numbers were observed among 12 AIDS-defining illnesses, oral candidiasis, and asymptomatic infection, allowing them to be grouped into five general catgories based on mean CD4 count: (a) asymptomatic infection (ASX) - CD4 greater than 500/mm3; (b) oral candidiasis (O-C) and tuberculosis (TB) - range 250-500/mm3; (c) Kaposi's sarcoma (KS), lymphoma (LYM), and cryptosporidiosis (CRS) - range 150-200/mm3; (d) PCP, disseminated Mycobacterium avium complex (MAC), herpes simplex ulceration (HSV), toxoplasmosis (TOX), cryptococcosis (CRC), oesophageal candidiasis (E-C) - range 75-125/mm3; (e) cytomegalovirus retinitis - less than 50/mm3 (Crowe et al. 1991). This correlation depicted in Graph 12.1, can explain the relative difference in occurrence of TB and PCP in Africa as compared with Europe.

The risk of development of PCP in immunodeficient patients with CD4 counts below 200 motivates prophylactic treatment (Guss 1994). This has led not only to a decrease in PCP

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prevalence but also to extrapulmonary P. carinii infections. Prior to the advent of the HIV-1 epidemic, only 16 cases of extrapulmonary Pneumocystosis had been reported in individuals who were immunocompromised by a variety of underlying diseases. Since the beginning of the HIV-1 and related PCP epidemic, at least 90 cases of extrapulmonary pneumocystosis have been reported (Ng et al. 1997). The central role played by CD4 T-lymphocytes is illustrated by the observed relationship between CD4 T-lymphocyte counts and the time of appearance of opportunistic infections. There is a definite clinical association of PCP with low CD4 lymphocyte counts as described above. The major surface glycoprotein of Pneumocystis can induce a protective CD4 T-cellular immunity mediated by IFN-g, which has several identified protective effects. IFN-g has an effect on macrophages, activating them to produce toxic superoxide intermediates and NO which are toxic to Pneumocystis. IFN-g also has an effect on the expression of integrins on alveolar cells, thereby decreasing receptor-mediated binding of the parasites. Thus lack of IFN-g in experimental Pneumocystosis is a typical interstitial cell pneumonia. Antibody-mediated killing of Pneumocystis is another protective mechanism, even if its relative role appears to be varied under different conditions, depending on the type of immunodeficiency. In experimentally induced immunodeficiency caused by simian immunodeficiency virus, SIV, the monkey equivalent of HIV infection, the CD4 cell counts of <50 cellsM was associated with PCP, cytomegalovirus meningoencephalitis, lymphoid depletion, and thymic atrophy (Shibata et al. 1997). Two hypotheses, which are not mutually exclusive, have been advanced to explain the development of PCP in immunosuppressed patients: activation of a latent infection and de novo infection. Reactivation, in analogy to the relationship between immunosuppression and toxoplasmosis, is assumed to be related to the demonstrated seropositivity developing in children (see above) and to some experimental studies demonstrating latent infections in immunosuppressed rats (Frenkel et al. 1966). Experimental studies suggest that the activation of a latent infection of P. carinii occurs in SIV-infected rhesus monkeys: PCR-based methods and P. carinii-specific bands of DNA amplification, but not histopathologic examination, detected P. carinii in the liver, kidney, spleen, adrenal gland, testis, brain, and other organs examined (Furuta et al. 1993). However, no P. carinii. could be detected with monoclonal antibodies and PCR in broncho-alveolar lavage fluid (BAL) and autopsy lung tissue from immunocompetent subjects (Millard and Heyret 1988; Peters et al. 1992).

Several observations support the hypothesis of de novo infection. The host immune response to P. carinii can completely eliminate the organism from the host (Chen et al. 1993), and in animal experiments the normal host is capable of clearing the organism within a year (Vargus et al. 1995) It has been suggested that Pneumocystis infection might be acquired, as deep mycoses, from environmental sources through the respiratory tract (Dei Cas et al. 1992).

In the literature there are several reports consistent with nosocomial transmission and outbreaks. An outbreak of PCP in three patients within a 6-week period was reported. Two patients had acute lymphoblastic leukaemia and one had brain-stem glioma. They shared common features of immunosuppression and absence of cotrimoxazole prophylaxis and had been nursed in the same room (Cheung et al. 1994).

There are reports of outbreaks of PCP in hospitals and the genetically distinct genotypes associated with both separate and recurrent episodes of PCP (Keely et al. 1995, 1996; Tsolaki et al. 1996; Keely and

Stringer 1997; Latouche et al. 1997d) favour the concept of de novo infection. In some of these reports, person-to-person transmission of P. carinii was considered likely (Hirschl et al. 1992; Hennequin et al. 1995).

We, like others, have encountered difficulties in inducing experimental PCP using the classical immunosuppression regimens published by several workers. Our initial failure to induce PCP in immunosuppressed rats was followed by success when P. carinii-infected rats obtained from Costa Rica were housed together with non-infected immunosuppressed rats in Helsinki (Sukura et al. 1991b). Hughes has already demonstrated in 1982 that rats acquire P. carinii infection by an air-borne route and eliminated food, water, and soil as sources of infection (Hughes 1982). The air-borne mode of transmission is further supported by recent experiments with SIV-infected rhesus macaques (Vogel et al. 1993) and with 'sentinel' rats housed near immunosuppressed P. carinii-infected rats (Sepkowitz 1993). Transient carriage of P. carinii may occur in immunocompetent rats housed near immunosuppressed P. carinii-infected rats. Within 6 weeks, P. carinii DNA became detectable in the lungs and by 8 weeks, in the blood. Pneumocystis carinii DNA disappeared rapidly from the lungs and sera after sentinel rats were isolated away from corticosteroid-treated rats. Sporadic findings of P. carinii in human immunocompetent hosts are also reported ( Jacobs et al. 1991; Calderón et al. 1996; Heresi et al. 1997). High levels of anti-P. carinii antibody titres were seen in health care staff working in AIDS units (Leigh et al. 1993), but this was not confirmed in a Scandinavian study, where attempts to demostrate P. carinii DNA in sputa also failed (Lundgren et al. 1997).

The hypothesis that P. carinii infection is acquired through the inhalation of air containing the infectious stage of the parasite, fits with the reclassification of P. carinii as a fungus. There is accumulating direct evidence for an air-borne route of transmission. The DNA of P. carinii has been demonstrated not only in the air surrounding both P. carinii-infected rats and patients with PCP but also in air samples from rural locations (Bartlett et al. 1996b; Olsson et al. 1996; Wakefield 1996). Even stronger evidence for air-borne transmission is the demonstated presence of the same species-specific genotypes of P. carinii in the air and in infected individuals. This has been shown both in experimentally infected rabbits and rats (Latouche et al. 1997a) and in patients with (Bartlett et al. 1997; Olsson et al 1998). An obvoius question is, what is the transmissive stage of P. carinii? So far there is no conclusive answer. It is remarkable that infected lungs containing the two identified stages of the organism, cysts or asci and the trophic form, are not very infectious, for example, Hughes (1982) showed that rats were infected through air, but failed to induce the infection by exposing rats to infected lung tissue.

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