In this paper, we present the first detailed review of HIV-infected patients with pulmonary cryptococcosis reported since the widespread introduction of ART in Sub-Saharan Africa. We found that the prevalence of pulmonary cryptococcosis among all HIV-infected patients hospitalized with pneumonia who underwent bronchoscopy was 11%. The diagnosis of pulmonary cryptococcosis was not suspected in any of these 15 patients prior to diagnostic testing, and known survival of the patients with pulmonary cryptococcosis was low (9/15, 60% at six months). However, 33% of the patients with pulmonary cryptococcosis improved without anti-fungal therapy up to six-month follow-up. This finding was unexpected and suggests that some HIV-infected patients with Cryptococcus isolated from respiratory samples may have localized infection or colonization.
In previous clinical studies from Sub-Saharan Africa prior to ART introduction, the prevalence of pulmonary cryptococcosis ranged from 0 to 13% in HIV-infected patients with respiratory symptoms.9–11
While the number of cryptococcosis cases has declined significantly in the United States following the introduction of ART, cases continue to be diagnosed in individuals with limited access to health care.12
In our study, only 22 (17%) patients overall and none of the 15 patients who had C. neoformans
isolated from BAL fluid were receiving ART at the time of hospital admission. Moreover, the median CD4+ T-lymphocyte count of our study sample indicates an advanced level of immunosuppression. Since access to ART remains limited in Uganda despite the initiatives to scale up distribution, it is not surprising that the prevalence of pulmonary cryptococcosis among HIV-infected patients with pneumonia remains high.
In spite of its high prevalence in this population sample, the diagnosis of pulmonary cryptococcosis was not suspected in any patient at the time of hospital admission. Many clinicians in Sub-Saharan Africa may be unaware of the epidemiology of pulmonary cryptococcosis. In South Africa, clinicians suspected the diagnosis of pulmonary cryptococcosis prior to death in only one percent of patients who had pulmonary cryptococcosis confirmed by autopsy.13
We found, as have others, that the clinical symptoms, physical exam findings, and radiographic manifestations of pulmonary cryptococcosis are non-specific and similar to those of other opportunistic pulmonary diseases, reinforcing the importance of establishing a confirmed microbiologic diagnosis whenever possible.14–18
Therefore, clinicians should maintain a high index of suspicion for pulmonary cryptococcosis, particularly among patients with very advanced immunosuppression (CD4+ T-lymphocyte count < 50 cells/µL).
In our study, five of 13 patients had improved at six-months without anti-fungal treatment, and all five had initiated ART. One potential explanation for this unexpected finding is that ART-associated immune reconstitution enabled clearance of C. neoformans
from the lungs. ART and the resulting immune reconstitution has been shown to be successful and is recommended as first-line therapy for several opportunistic infections such as cryptosporidiosis, microsporidiosis, and progressive multifocal leukoencephalopathy (PML) for which effective antimicrobial therapies are lacking. Zolopa et al reported that early ART was associated with fewer deaths or progressions to AIDS at 48 weeks compared to deferred ART in HIV-infected patients presenting with an acute opportunistic infection.19
However, three mortality studies done in Uganda on cryptococcosis after initiation of ART have shown disappointing results. One study found that the mortality of cryptococcal meningitis remained high despite the availability of ART.20
Another study found that asymptomatic cryptococcal antigenemia was an independent risk factor associated with an increased mortality during the first 12 weeks of ART.21
A third study reported that five out of five HIV infected patients with CD4+ T-lymphocyte counts ≤ 100cells/µL and asymptomatic cryptococcal antigenemia died within two months after starting ART without fluconazole treatment.22
Taken together, these data suggest that ART alone is insufficient to eradicate disseminated C. neoformans
infection from patients with advanced immunosuppression but that it may be sufficient for C. neoformans
infection limited to the lungs.
We assume that the five patients who improved without antifungal medicine in spite of their low CD4+ T lymphocyte counts in our study did not have disseminated disease, but instead had localized infection or colonization of the airway by Cryptococcus
. Another possibility is that the fungal cultures were false positive and represent laboratory contamination. We cannot rule out the possibility of precipitation of Cryptococcus
from the environment on to the plates during the procedure of inoculation because C. neoformans
has been isolated from house dust in Central Africa.23, 24
However this possibility is unlikely because dust collection for Cryptococcus
culture needs large amounts (200–283 liters) of air exchange25
and the inoculation time was short.
While isolating C. neoformans
from cerebrospinal fluid has been shown to be highly specific for cryptococcal meningitis1
, the significance of isolating C. neoformans
from respiratory specimens has not been well established. Because the lungs are the portal of entry, C. neoformans
organisms may be found in the airways in the absence of disease. A definitive diagnosis of cryptococcal pneumonia may require identification of the organism in tissue obtained from a biopsy or a surgical specimen.26, 27
In practice, experts advocate treatment whenever respiratory specimens grow C. neoformans
in the setting of a compatible clinical syndrome in HIV-infected patients.28, 29
However, the potential presence of co-infections in HIV-infected patients makes it difficult to define a “compatible clinical syndrome.” Of 15 pulmonary cryptococcosis patients in our study, eight (53%) had two pulmonary processes. In these patients, it is unclear whether the clinical and radiographic findings were due to cryptococcosis, the other pulmonary process, or both. No study has proved the presence of colonization of C. neoformans
in the airways of HIV-infected patients, though colonization of the nasopharynx has been documented.30
Further studies and expert consensus are needed to define the significance of isolating C. neoformans
from respiratory specimens.
The possibility of localized infection or colonization of C. neoformans
in the airway of HIV-infected patients calls into question the principle that all HIV-infected patients with pulmonary cryptococcosis need antifungal treatment. Whether to “treat or observe” is a difficult decision in HIV-negative patients with pulmonary cryptococcosis because of the difficulty in distinguishing infection from colonization.31, 32
This decision is more difficult in HIV-infected patients, given the high mortality associated with cryptococcosis in this population. CD4+ T lymphocyte counts and serum cryptococcal antigen test may be of help in making a right decision.
There are some limitations to our study. First, we did not perform serum cryptococcal antigen testing, which might have helped us differentiate between isolated pulmonary disease and disseminated disease. Second, we did not determine the serotype of C. neoformans
isolates obtained during our study. A previous study from Uganda showed that all 36 cryptococcal isolates causing disease were confirmed C. neoformans var grubii
, serotype A.4
Last, the small number of patients in this series limited our statistical power to identify clinical and radiographic characteristics that might differentiate those with pulmonary cryptococcosis from those with other respiratory infections.
In summary, pulmonary cryptococcosis is common in HIV-infected TB suspects in Uganda and should be considered in the differential diagnosis of HIV-infected individuals with pneumonia. Additional studies should determine whether initiation of ART without antifungal therapy is sufficient treatment for patients with pulmonary cryptococcosis without evidence of disseminated disease.