Category Archives: 11. Opportunistic Infections

Progressive multifocal Leukoencephalopathy

– Christian Hoffmann –

PML is a severe demyelinating disease of the central nervous system. It is caused by JC virus (JCV), a polyoma virus found worldwide. JCV was named after the initials of the first patient John Cunningham, from which this simple DNA virus was first isolated in 1971 (Major 1992). Therefore, JC has no connection, as is often wrongly assumed, with Jakob-Creutzfeld syndrome. As seroprevalence is high, at up to 80%, latent persistent infection is assumed. Kidneys and bones seem to be important reservoirs. Only impaired cellular immunity leads to reactivation of JCV and manifestation of disease. It seems certain that JCV reaches the CNS via leukocytes, and then affects mainly oligodendrocytes and consequently the cells which comprise the myelin sheaths. Destruction of these is as macroscopically apparent as multifocal demyelination. The main focus of the disease is the white matter of the cerebral hemispheres, but in some cases, the cerebellum, the grey matter may also be affected.

PML is a classic opportunistic infection and can occur in patients with hematological diseases or during therapy with monoclonal antibodies such as rituximab, natalizumab or efalizumab (Yousry 2006, Carson 2009, Major 2010). However, HIV patients are by far the largest patient group. Severe immunodeficiency is frequently seen, but not obligatory for development of PML. In contrast to CMV or MAC infection, PML does not always indicate the final stages of HIV infection. Although CD4 T cells are usually below 100/µl at manifestation of disease, PML may also occur at above 200 CD4 T cells/µl. The decrease in incidence is not as marked as with other OIs. After cerebral toxoplasmosis, it is now probably the second most common neurological OI (Antinori 2001).

Prognosis was poor in the pre-HAART era. The median interval between the onset of the first symptoms and death was between 3 and 6 months. Patients usually died of secondary complications after being bedridden for many weeks. The prognosis is slightly better at CD4 counts above 200/µl (Berger 1998). Disease progression seems to be much slower under ART, and even complete remission seems possible (Albrecht 1998). However, these effects are not as impressive as for other OIs: in a Spanish study of 118 PML patients on ART, 64% were still alive 2.2 years after diagnosis (Berenguer 2003). Complete remissions are not the rule, even under sufficient ART. They mainly occur in cases of inflammatory PML, which occurs in the course of an immune reconstitution inflammatory syndrome (Du Pasquier 2003, Hoffmann 2003, Tan 2009). The number of CD4 T-cells and the JC-virus specific immune response seem to be relevant as prognostic markers, however the JCV viral load does not seem relevant (Khanna 2009, Marzocchetti 2009). Today PML is still the OI with the highest mortality (ART-CC 2009).

Signs and symptoms

Although there is a broad spectrum of PML symptoms due to the variety of localized areas of demyelination, the clinical signs and course of the disease have several common characteristics. In addition to cognitive disorders, which may range from mild impairment of concentration to dementia, focal neurological deficits are very typical of PML. Mono- and hemiparesis are observed most frequently, as well as speech and even visual deficits. We have seen several blind patients with PML. These deficits may be isolated and initially present as discrete changes in coordination, rapidly leading to considerable disabilities. Epileptic seizures may also occur. Loss of sensibility, fever, and headache are rare and are usually more typical of cerebral toxoplasmosis.

Diagnosis

Clinical suspicion of PML should be rapidly confirmed radiologically. But beware: a CCT scan is not helpful – it does not clearly reveal hypodense lesions. A MRI is much more sensitive to detecting both the number and size of lesions than a CCT and usually shows high signal intensity lesions in T2-weighted imaging and in FLAIR sequence, which are hypointense in T1-w and often do not show gadolinium enhancement or mass effect. ART may result in inflammatory courses that involve significant enhancement (see IRIS). Exclusion of grey matter is typical – since this is a leukoencephalopathy. Furthermore, it should be noted that the lesions are almost always asymmetrical.

A MRI often allows distinction from cerebral toxoplasmosis or lymphoma. However, the huge, extensive lesions covering an entire hemisphere that are often shown in the literature are not always present. Every PML starts small – very discrete, localized, solitary lesions can occur and certainly do not exclude the diagnosis. PML can occur everywhere in the brain, and there are no typically susceptible areas. Lesions are often parieto-occipital or periventricular, but the cerebellum may also be involved. It is important that the images are assessed by a radiologist or clinician familiar with PML. Even then, it is difficult to distinguish PML from HHV-6 infection (Caserta 2004) or HIV leukoencephalopathy (Langford 2002).

Clinicoradiological diagnosis is therefore not definitive. Examination of cerebrospinal fluid is essential. Generally, if there is no other co-infection, then unspecific inflammatory signs are absent, although the total protein content is usually slightly elevated. Pleocytosis is rarely seen, and more than 100/3 cells make PML unlikely. CSF should always be tested for JCV. Newer PCR methods have a sensitivity of around 80% and a specificity of over 90%. A CSF sample should be sent to a JCV-experienced laboratory.

PML is very probable in cases of clinicoradiological suspicion and positive JCV PCR. In such cases, brain biopsies are no longer recommended today. Nevertheless, negative PCR does not exclude the diagnosis. Levels of JCV viral load may vary significantly and do not correlate with the extent of lesions (Eggers 1999, Garcia 2002, Bossolasco 2005). Unfortunately, JCV PCR is even less useful – many patients with PML have a low or undetectable JCV CSF viral load under ART (Bossolasco 2005). Stereotactic brain biopsy may become necessary in individual cases.

Treatment

A specific PML treatment is not available. Foscarnet, interferon, immune stimulants, steroids or cytosine-arabinoside are not effective (Hall 1998). Cidofovir and camptothecin are the two new drugs currently being discussed. It is feared that these drugs will have a similar fate in controlled studies. Camptothecin is an alkaloid cytostatic, which inhibits topoisomerase I, a nuclear enzyme that is required for DNA and therefore also JCV replication (O’Reilly 1997). Currently, only data from case studies and a small series of patients exist in which 3 out of 12 patients experienced clinical improvement under the camptothecin-derivate topotecan (Vollmer-Haase 1997, Royal 2003). However, one patient died under topotecan, which shows high hematoxicity. Results of randomized studies are missing and this approach can not be recommended outside clinical studies.

The nucleotide analog cidofovir, which is licensed for cmv retinitis showed some positive effects. According to an analysis of 370 patients from numerous studies (De Luca 2008), a real benefit has not been proven Observed experiences have been rather disappointing and, in a retrospective analysis of 35 patients, cidofovir was even associated with a poorer prognosis. However, this chiefly reflects the frustration of patients and clinicians – cidofovir was mainly used in cases of progressive disease (Wyen 2004). Furthermore, the opinion exists that there is no longer an argument for the use of cidofovir in PML patients.

In recent years, 5-HT2a-inhibitors and/or serotonin receptor antagonists have been proposed for PML treatment. It has been shown that the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells (Elphick 2004); the blockade could represent thus a therapeutic goal. Case studies for some agents such as risperidone and mirtazapine, which block serotonergic receptors, exist already (Verma 2007, Focosi 2007+2008, Cettomai 2009). However, controlled studies are missing. This is also the case for mefloquine (Brickelmeier 2009).

The absolute priority should currently be to optimize ART in cases of PML. Improvement of the JC virus-specific immune response which is often observed within immune reconstitution determines the patient’s further progress to a large extent (Khanna 2009, Marzocchetti 2007+2009). Our early observation that prognosis significantly improved under ART (Albrecht 1998) was confirmed by several other groups (Clifford 1999, Dworkin 1999, Gasnault 1999+2008, Tantisiriwat 1999, Berenguer 2003, Khanna 2009). Since synergism between HIV and JCV has been demonstrated in vitro, maximal HIV suppression should at least be achieved. Although progression of disease has been described under sufficient antiretroviral therapy, ART often remains the only real hope for patients today. There is also some evidence that intracerebral penetrating antiretroviral agents such as AZT, FTC, abacavir, nevirapine and lopinavir are more efficient on survival of PML patients (Gasnault 2008).

Treatment/prophylaxis of PML
Acute therapy    
Treatment of choice ART The most important goal is maximal HIV suppression and immune reconstitution. Use intracerebral penetrating agents such as AZT, FTC, abacavir, nevirapine and lopinavir
Experimental   Only within clinical trials (risperidone? mirtazapine?)
Prophylaxis   Not available

Prophylaxis

There is none. Exposure prophylaxis is also not possible.

References

Albrecht H, Hoffmann C, Degen O, et al. HAART significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS 1998, 12:1149-1154.

Antinori A, Ammassari A, Giancola ML, et al. Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. J Neurovirol 2001, 7:323-8.

Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003, 36: 1047-52.

Berger JR, Levy RM, Flomenhoft D, et al. Predictive factors for prolonged survival in AIDS-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998, 44:341-9.

Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005, 40:738-44.

Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009, 53:1840-9.

Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy following rituximab therapy in HIV negative patients: a report of 57 cases from the Research on Adverse Drug Event and Reports (RADAR) project. Blood 2009 Mar 5.

Caserta MT. Human Herpesvirus 6 Infection of the Central Nervous System. Curr Infect Dis Rep 2004, 6: 316-321.

Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009, 66:255-8.

Clifford DB, Yiannoutsos C, Glicksman M et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 1999, 52:623-5.

De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008, 22:1759-67.

Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003; 9 Suppl 1:25-31.

Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive multifocal leukoencephalopathy: improved survival of HIV-infected patients in the protease inhibitor era. J Infect Dis 1999, 180:621-5.

Eggers C, Stellbrink HJ, Buhk T, Dorries K. Quantification of JC virus DNA in the cerebrospinal fluid of patients with HIV-associated PML – a longitudinal study. J Infect Dis 1999, 180:1690-4.

Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004;306:1380-3.

Engsig FN, Hansen AB, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 2009, 199:77-83.

Falcó V, Olmo M, del Saz SV, et al. Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J AIDS 2008, 49:26-31.

Focosi D, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. Risperidone-induced reduction in JC viruria as a surrogate marker for efficacy against progressive multifocal leukoencephalopathy and hemorrhagic cystitis. J Clin Virol 2007; 39:63–4.

Focosi D, Kast RE, Maggi F, et al. 5-HT2a inhibitors for progressive multifocal leukoencephalopathy: old drugs for an old disease. J Infect Dis 2008, 197:328.

Garcia De Viedma D, Diaz Infantes M, Miralles P, et al. JC virus load in progressive multifocal leukoencephalopathy: analysis of the correlation between the viral burden in cerebrospinal fluid, patient survival, and the volume of neurological lesions. Clin Infect Dis 2002, 34:1568-75.

Gasnault J, Lanoy E, Bentata M, et al. Intracerebral penetrating ART are more efficient on survival of HIV+ patients with progressive multifocal leucoencephalopathy. Abstract 385, 15th CROI 2008, Boston.

Gasnault J, Taoufik Y, Goujard C, et al. Prolonged survival without neurological improvement in patients with AIDS-related PML on potent combined antiretroviral therapy. J Neurovirol 1999, 5:421-9.

Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with HIV infection. N Engl J Med 1998, 338:1345-51.

Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003;74:1142-4.

Khanna N, Elzi L, Mueller NJ, et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis 2009, 48:1459-66.

Khanna N, Wolbers M, Mueller NJ, et al. JCV-specific immune responses in hiv-1 patients with progressive multifocal leukoencephalopathy. J Virol 2009 Feb 11. [Epub ahead of print]

Langford TD, Letendre SL, Marcotte TD, et al. Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 2002, 16:1019-29.

Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 1992, 5:49-73.

Marzocchetti A, Sanguinetti M, Giambenedetto SD, et al. Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis. J Neurovirol 2007;13:338-46.

Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009, 73:1551-8.

O’Reilly S. Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 350:291.

Royal W 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9:411-9.

Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology 2009 Jan 7.

Tantisiriwat W, Tebas P, Clifford DB, et al: Progressive multifocal leukoencephalopathy in patients with AIDS receiving HAART. Clin Infect Dis 1999, 28:1152-4.

Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007;196:709-11.

Vollmer-Haase J, Young P, Ringelstein EB. Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 349:1366.

Wyen C, Hoffmann C, Schmeier N, et al. Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. J AIDS 2004, 37:1263-1268.

Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006, 354:924-33.

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Filed under 11. Opportunistic Infections, Part 3 - AIDS, Progressive multifocal Leukoencephalopathy

Cryptosporidiosis

– Christian Hoffmann –

Cryptosporidiosis is a parasitic intestinal disease with fecal-oral transmission. It is mainly caused by the protozoon Cryptosporidium parvum (two genotypes exist, genotype 1 is now also known as C. hominis), and may affect both immunocompetent and immunocompromised hosts (review: Chen 2002). First described in 1976, cryptosporidia are among the most important and most frequent causes of diarrhea worldwide. Important sources of infection for this intracellular parasite include animals, contaminated water and food. The incubation period lasts approximately 10 days. While diarrhea almost always resolves within a few days in otherwise healthy hosts or in HIV infected patients with CD4 counts greater than 200 cells/µl, cryptosporidiosis is often chronic in AIDS patients. Particularly in severely immunocompromised patients (below 50 CD4 T cells/µl), diarrhea may become life threatening due to water and electrolyte losses (Colford 1996). Only chronic, and not acute, cryptosporidiosis is AIDS-defining.

Signs and symptoms

The typical watery diarrhea can be so severe that it leads to death as a result of electrolyte loss and dehydration. Up to twenty bowel movements a day are not uncommon. Tenesmus is frequent, along with nausea and vomiting. However, the symptoms are highly variable. Fever is usually absent. Additionally, the biliary ducts may occasionally be affected with the elevation of biliary enzymes. Pancreatitis is also possible.

Diagnosis

When submitting stool samples, the laboratory should be informed of the clinical suspicion. Otherwise, cryptosporidia are often overlooked. If the laboratory is experienced and receives the correct information, then usually just one stool sample is sufficient for detection. In contrast, antibodies or other diagnostic tests are not helpful. The differential diagnosis should include all diarrhea-causing pathogens.

Treatment

No specific treatment has been established to date. Diarrhea is self-limiting with a good immune status; therefore, poor immune status should always be improved with ART – and this often leads to resolution (Carr 1998, Miao 2000). To ensure absorption of antiretroviral drugs, symptomatic treatment with loperamide and/or opium tincture , a controlled drug prescription at its maximum dosage, is advised. If this is unsuccessful, then treatment with other anti-diarrheal medications, perhaps even sandostatin, can be attempted. Sufficient hydration is necessary and infusions may even be required.

Recent reviews confirmed the absence of evidence for effective agents in the management of cryptosporidiosis (Abubakar 2007, Pantenberg 2009). We have observed good results with the antihelminthic agent nitazoxanide (Cryptaz®). Nitazoxanide proved to be effective in a small, randomized study (Rossignol 2001). In 2005 it was licensed in the USA for treatment of cryptosporidia associated diarrhea in immunocompetent patients. Nitazoxanide is not approved to AIDS patients and showed no effects in a double blind randomized study in HIV infected children with cryptosporidia (Amadi 2009).

Rifaximine (Xifaxan®, 200 mg) is a nonabsorbed rifampicin derivative, already licensed in the US as an anti-diarrheal. The first data with AIDS patients are very promising (Gathe 2008).

Paromomycin (Humatin®) is a nonabsorbed aminoglycoside antibiotic and has shown favorable effects on diarrhea in small uncontrolled studies (White 2001). In one double-blind randomized study, however, there was no advantage over placebo (Hewitt 2000). Potentially, there is an effect in combination with azithromycin (Smith 1998).

Treatment/prophylaxis of cryptosporidiosis (daily doses)
Acute therapy    
Symptomatic Loperamide +

 
opium tincture

Loperamide 1 cap at 2 mg 2–6 times daily or

loperamide solution 10 ml (10 ml = 2 mg)
2–6 times daily and/or

Opium tincture 1% = 5–15 drops qid

Symptomatic Octreotide Sandostatin solution for injection 1 amp at 50 µg s.c. bid or tid (increase dose slowly)
Curative attempt Nitazoxanide Nitazoxanide1 tbl. at 500 mg bid
Curative attempt Rifaximin Rifaximin 2 tbl. at 200 mg bid
Prophylaxis   Exposure prophylaxis: no tap water

Prophylaxis

There is no generally accepted prophylaxis, although retrospective analyses have reported a protective effect of rifabutin and clarithromycin (Holmberg 1998). The importance of good hygiene and not drinking tap water should be emphasized to patients, at least in countries with limited access to clean, adequate drinking water. Contact with human and animal feces should be avoided. The tendency for patients to become ill during the summer months can often be linked to swimming in rivers or lakes. Cryptosporidia are resistant to most disinfectants. In hospitals and other medical facilities, the usual hygienic measures, such as wearing gloves, are adequate. Moreover, patients do not need to be isolated. However, they should not be put in the same room with other significantly immunocompromised patients.

References

Abubakar I, Aliyu SH, Arumugam C, Usman NK, Hunter PR. Treatment of cryptosporidiosis in immuno-compromised individuals: systematic review and meta-analysis. Br J Clin Pharmacol 2007;63:387-93.

Amadi B, Mwiya M, Musuku J, et al. Effect of nitazoxanide on morbidity and mortality in Zambian children with cryptosporidiosis: a randomised controlled trial. Lancet 2002, 360:1375-1380.

Amadi B, Mwiya M, Sianongo S, et al. High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial. BMC Infect Dis 2009, 9:195.

Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1 associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998, 351:256-61.

Chen XM, Keithly JS, Paya CV, LaRusso NF. Cryptosporidiosis. N Engl J Med 2002, 346: 1723-31.

Colford JM Jr, Tager IB, Hirozawa AM, et al. Cryptosporidiosis among patients infected with HIV. Factors related to symptomatic infection and survival. Am J Epidemiol 1996, 144:807-16.

Gathe JC Jr, Mayberry C, Clemmons J, Nemecek J. Resolution of severe cryptosporidial diarrhea with rifaximin in patients with AIDS. J AIDS 2008, 48:363-4.

Griffiths JK. Treatment for AIDS-associated cryptosporidiosis. J Infect Dis 1998, 178:915-6.

Hewitt RG, Yiannoutsos CT, Higgs ES, et al. Paromomycin: No more effective than placebo for treatment of cryptosporidiosis in patients with advanced HIV infection. Clin Inf Dis 2000, 31:1084-92.

Holmberg SD, Moorman AC, Von Bargen JC, et al. Possible effectiveness of clarithromycin and rifabutin for cryptosporidiosis chemoprophylaxis in HIV disease. JAMA 1998, 279:384-6.

Miao YM, Awad-El-Kariem FM, Franzen C, et al. Eradication of cryptosporidia and microsporidia following successful antiretroviral therapy. J Acquir Immune Defic Syndr 2000, 25: 124-9.

Pantenburg B, Cabada MM, White AC Jr. Treatment of cryptosporidiosis. Expert Rev Anti Infect Ther 2009, 7:385-91.

Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, placebo-controlled study of Nitazoxanide. J Infect Dis 2001, 184:103-6.

Smith NH, Cron S, Valdez LM, Chappell CL, White AC Jr. Combination drug therapy for cryptosporidiosis in AIDS. J Infect Dis 1998, 178:900-3.

White AC, Cron SG, Chappell CL. Paromomycin in cryptosporidiosis. Clin Inf Dis 2001, 32:1516-7.

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Filed under 11. Opportunistic Infections, Cryptosporidiosis, Part 3 - AIDS

Cryptococcosis

– Christian Hoffmann –

Infection with the yeast Cryptococcus neoformans is a rare AIDS-defining illness in Europe. In the US and especially in Southeast Asia, cryptococcosis occurs much more frequently and is considerably one of the more prominent AIDS-defining illnesses worldwide. Presumably transmitted via inhalation, bird droppings are a key reservoir for C. neoformans. This pulmonary infection may remain subclinical in immunocompetent patients, but is almost always followed by disseminated disease in HIV patients. Apart from the lungs, the main manifestation after hematogenic spread is in the CNS. For this reason, a CSF examination is obligatory in every suspected case. However, isolated skin manifestations and lymphadenitis can also occur. Organ involvement, such as in the urogenital or gastrointestinal tract, is rare.

Cryptococcosis almost always occurs with severe immunodeficiency. In a collection of 114 cases, 87% had less than 100 CD4 T cells/µl; the median CD4 count was 30/µl (Weitzel 1999). Cryptococcosis is fatal if untreated. Treatment is lengthy, complicated and should managed only on an inpatient basis. Relapses were frequent in the pre-HAART era and occurred in at least 15% of cases. In addition, cryptococcosis occurs relatively frequently in the presence of an immune reconstitution inflammatory syndrome. Prognosis has much improved over the last years. In one study from France, the mortality rate per 100 person-years was 15.3 in 1996-2000, compared with 63.8% in the pre-HAART era although early mortality did not differ between the two periods (Lortholary 2006).

Signs and symptoms

The CNS manifestation with encephalitis is the most frequent manifestation (ca. 80%). Patients complain mainly of headaches, fever and confusion or clouding of consciousness which progresses rapidly over a few days. Disorders of gait, hearing, and vision may occur, as well as paresis, particularly of the cranial nerves, in such cases intracranial pressure is almost always increased. However, meningeal symptoms are usually absent. In the course of an immune reconstitution syndrome, clinical symptoms are often atypical and characterized by extensive abscesses (Manfredi 1999).

Pulmonary disease leads to symptoms of atypical pneumonia with unproductive cough and chest pain. Skin lesions can initially resemble molluscum contagiosum, and later become confluent in the form of larger, ulcerative lesions.

Diagnosis

Cryptococcosis is life threatening, and the mortality rate in larger studies is between 6 and 25% (Saag 2000). There is no time to lose during diagnostic testing. Rapid examination of the lungs (HR-CT) and CNS in particular (MRI) should be initiated in every suspected case (e.g. positive cryptococcal antigen test).

The chest x-ray usually does not reveal much; therefore, an HRCT scan must be performed if pulmonary involvement is suspected. The spectrum of morphology on the image is very variable. Diffuse, small lesions similar to tuberculosis may occur, but there can also be sharply defined infiltrates reminiscent of bronchopneumonia. Cavitation and bronchiectasis may also be present. Every attempt should therefore be made to clearly identify the causative organism by BAL.

An MRI scan of the head should always be performed if there are neurological symptoms. However, in contrast to toxoplasmosis and primary CNS lymphoma, it usually does not reveal much, and isolated or multiple mass lesions (cryptococcomas) are very rare. Nevertheless, intracranial pressure is often increased and a fundoscopy (papillary edema) should be performed.

The most important test for cryptococcosis is lumbar puncture after a fundoscopy and/or an MRI. Diagnosis can be made via India ink stain in almost all cases. CSF must be examined even in cases with pulmonary or other manifestation to exclude CNS involvement. Cryptococcal antigen in the blood (titer > 1:8) is a good parameter and should always be determined. Blood cultures are also often positive. With cutaneous involvement, the diagnosis is usually made from a biopsy.

Treatment

In cases of CNS involvement an immediate combination of antimycotics is urgently recommended followed by maintenance therapy with fluconazole (Saag 2000). Fluconazole alone is not sufficient, as recently shown by two randomized trials from Africa. In these trials, mortality of cryptococcal meningitis was unacceptable high. Within the first weeks, 54-59% of the patients died (Longley 2008, Makadzange 2009).

Combination prevents resistance and allows reduction of acute therapy to 4-6 weeks. The choice of combination is not clearly defined. In some countries, combination therapy with the three antimycotics amphotericin B, flucytosine and fluconazole is often used for meningitis. The triple therapy leads to complete remission of meningitis in around 80% of cases (Weitzel 1999), and consequently the possibility of a slightly higher rate than under dual therapy with amphotericin B and flucytosine as favored in the United States (van der Horst 1997).

However, other data is raising questions as to the superiority of triple therapy. According to the measurements of cryptococcal clearance in the CSF, in a small, randomized study of 64 patients in Thailand, the combination of amphotericin B and flucytosine was the most effective treatment (Brouwer 2004). It was even significantly better than triple therapy and also amphotericin B and fluconazole. Amphotericin B at a dosage of 1 mg/kg plus is possibly more rapidly fungicidal than is standard-dose Amphotericin B (Bicanic 2008). If amphotericin B should not be available, the combination of flucytosine and fluconazole is better than fluconazole alone (Nussbaum 2010).

Nevertheless, in view of the toxicity of flucytosine which is only available in many countries for infusion and not in tablet form, the combination of amphotericin B and fluconazole is preferable. In a phase II study the high doses of 800 mg fluconazole daily was most effective (Pappas 2009). A newer study showed the efficacy of high dose fluconazole is equivalent to flucytosine (Loyse 2011).

In addition to having significantly lower toxicity, liposomal amphotericin (Ambisome®) is slightly more effective than conventional amphotericin B (Lenders 1997, Hamill 1999). However even Ambisome®-containing combinations are highly toxic. Daily monitoring of kidney- and liver enzymes, blood count and electrolytes are recommended. Fluconazol should be administered as an infusion, particularly if patients seem confused.

In untreated patients, ART is typically started during the acute phase of treatment. Caution should be taken with tenofovir, given an observed case of renal failure requiring dialysis after treatment with tenofovir and amphotericin B. Since there is also a higher risk for the development of IRIS, the optimal time for initiation of ART is still under debate. In ACTG 5164, early start of ART was of advantage (Zolopa 2009). In a small African study on seriously ill patients, however, mortality was increased in patients starting ART immediately after diagnosis (Makadzange 2010).

In cases of isolated pulmonary involvement (CSF negative) or other extracerebral manifestations, treatment without flucytosine can be completed the acute therapy with amphotericin B and fluconazole within two instead of four weeks. If there is a positive cryptococcal antigen test without evidence of CNS, pulmonary or other infection, then treatment can consist of fluconazole alone.

Treatment success is monitored based on the clinical course and repeated lumbar punctures. CSF is negative in approximately 60% of cases after two weeks (Saag 2000). When this is the case, maintenance therapy or secondary prophylaxis can be started, though not sooner than after four weeks of acute therapy. The quicker the CSF shows to be negative, the better the prognosis (Bicanic 2009). If there is increased intracranial pressure, then CSF drainage may become necessary (Graybill 2000). Steroids are ineffective (Saag 2000).

Prophylaxis

Exposure can presumably also not be prevented. As survival benefit was not demonstrated, primary prophylaxis against Cryptococcus neoformans is not recommended even in endemic areas such as Thailand (McKinsey 1999, Chariyalertsak 2002). Fluconazole is given as secondary prophylaxis or maintenance therapy. It is significantly more effective than itraconazole. For example, in a large randomized study, the relapse rate in the fluconazole arm was only 4% compared to 23% in the itraconazole arm, resulting in discontinuation of the study before completion (Saag 1999). Fluconazole can probably be discontinued with sufficient immune reconstitution (above 200 CD4 cells/µl, undetectable viral load for three to six months), as demonstrated in several studies (Aberg 2002, Kirk 2002, Vibhagool 2003, Mussini 2004), and after at least six months of maintenance therapy. It is prudent to check for cryptococcal antigen before stopping (Mussini 2004). Positive antigen tests require continuation of treatment as the risk of relapses is high, especially in patients with high antigen titres (Lortholary 2006).

Treatment/prophylaxis of cryptococcosis (daily doses, unless specified otherwise), see also Drugs section for further details!
Acute therapy   Duration: always at least six weeks
Treatment of choice Amphotericin B

 

 
+ fluconazole

+ flucytosine *

Amphotericin B  0.5-0.75 mg/kg qd or

liposomal amphotericin B 3 mg/kg qd (preparation by pharmacy) plus

fluconazole 1 bottle at 200 mg i.v. bid or

fluconazole 1 cap. at 200 mg bid  plus

flucytosine 1 bottle at 250 ml (2.5 g) i.v. qid

(= 100-150 mg/kg distributed in four separate doses)

Maintenance therapy Discontinuation possible from > 200 CD4 cells/µl > 3-6 months
Treatment of choice Fluconazole Fluconazole 1-2 cap. at 200 mg qd

 

Alternative Itraconazole Itraconazole 2 cap. at 100 mg bid
Primary prophylaxis Not recommended
*Note: We usually omit flucytosine. In this case the daily doses of fluconazole should be 800 mg. Instead, we begin with ART during the acute therapy phase in those patients, who are almost always ART naive.

References

Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with AIDS, following immunologic response to ART. J Infect Dis 2002, 185:1179-82.

Bicanic T, Muzoora C, Brouwer AE, et al.  Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis 2009, 49:702-9.

Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008, 47:123-30.

Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004, 363:1764-7.

Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis 2002, 34:277-84.

Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.

Hamill RJ, Sobel J, El-Sadr W, et al. Randomized double blind trial of Ambisome and amphotericin B in acute cryptococcal meningitis in AIDS patients. 39th ICAAC 1999, San Francisco; Abstract 1161.

Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002, 137:239-50.

Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997, 11:1463-71.

Longley N, Muzoora C, Taseera K, et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556-61.

Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 2006, 20:2183-91.

Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose 5-FC, voriconazole, and flucytosine, as second drugs given in combination with amphotericin b, to treatment of hiv-associated cryptococcal meningitis. Abstract 893, 18th CROI 2011, Boston.

Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010, 50:1532-8.

Manfredi R, Pieri F, Pileri SA, Chiodo F. The changing face of AIDS-related opportunism: cryptococcosis in the HAART era. Case reports and literature review. Mycopathologia 1999, 148:73-8.

McKinsey DS, Wheat LJ, Cloud GA, Itraconazole prophylaxis for fungal infections in patients with advanced HIV infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.

Mussini C, Pezzotti P, Miro JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with HAART: an international observational study. Clin Infect Dis 2004, 38:565-71.

Nussbaum JC, Jackson A, Namarika D, et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi. Clin Infect Dis 2010, 50:338-44.

Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2009, 48:1775-83.

Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999, 28:291-6.

Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000, 30:710-8.

van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the AIDS. N Engl J Med 1997, 337:15-21.

Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients treated with HAART: a prospective, multicenter, randomized study. Clin Infect Dis 2003, 36:1329-31.

Weitzel A, Arasteh K, Mertenskötter T, et al. Kryptokokkosen bei HIV-positiven Patienten in Deutschland – eine Auswertung 24 deutscher Zentren. In: Brockmeyer NH et al. HIV-Infekt, Springer-Verlag; 1999.

Zolopa A, Andersen J, Komarow L, et al. Immediate vs deferred ART in the setting of acute AIDS-related opportunistic infection: final results of a randomized strategy trial, ACTG A5164. 15th CROI 2008, Boston.

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Filed under 11. Opportunistic Infections, Cryptococcosis, Part 3 - AIDS

Salmonella septicemia

– Christian Hoffmann –

Infection with non-typhoid Salmonella, which typically only causes enteritis in healthy individuals, can lead to severe septicemia in immunocompromised patients (Jacobs 1985). A newer study indicates that impaired immunity against nontyphoidal Salmonella bacteremia in HIV infection results from excess inhibitory antibodies against Salmonella lipopolysaccharides, whereas serum killing of Salmonella is induced by antibodies against outer membrane proteins (MacLennan 2010).

In Central Europe, Salmonella septicemia is rare in HIV patients, and accounts for less than 1% of AIDS cases. In the Swiss cohort of over 9,000 patients, only 22 cases of recurring salmonellosis were documented over a period of nine years (Burkhardt 1999).

In Southern Europe as well as Africa, salmonellosis is much more frequent. Infected food, particularly poultry, is the most widely recognized as a long-established reservoir for Salmonella. In most cases, relapses are frequent. In addition to septicemia, atypical infections with osteomyelitis, empyema, pulmonary abscesses, pyelonephritis or meningitis have been described (Albrecht 1992, Nadelman 1985). Recurring, non-typhoid Salmonella septicemia is considered an AIDS-defining illness. The risk of recurrent septicemia decreased significantly in the ART era (Hung 2007).

Signs and symptoms/diagnosis

Patients are often severely ill. Chills and high fever are usually present. If treatment is delayed, then there is always a danger of septic shock. Diarrhea may be absent.

Blood cultures mainly lead to isolation of enteritis-causing Salmonella strains such as S. enteritidis and S. typhimurium. The pathogens causing typhoid or paratyphoid fever, S. typhi and S. paratyphi, are rare.

Treatment

Ciprofloxacin is the treatment of choice (Jacobson 1989). Although oral bioavailability is good, intravenous dosing is preferable. In the US the resistance situation is comparably good (Forrest 2009). In contrast to Asia, where rates of ciprofloxacin resistances have clearly increased and risen to up to 30% (Hung 2007). In these cases, cephalosporins such as cefotaxime or ceftriaxone have proven to  be effective.

Treatment/prophylaxis of Salmonella sepsis (daily doses)
Acute therapy 7-14 days
Treatment of choice Ciprofloxacin Ciprofloxacin 1 bottle at 200 mg i.v. bid
Alternative Ceftriaxone Ceftriaxone 1 bottle at 2 g i.v. qd
Prophylaxis For relapses
  Ciprofloxacin 1 tbl. at 500 mg bid (6-8 months)

One week of treatment with ciprofloxacin or ceftriaxone is usually enough. Maintenance therapy should continue for 6-8 months and not be stopped too early (Hung 2001). However, lifelong secondary prophylaxis, which was propagated in the past (Nelson 1992), no longer seems necessary.

Prophylaxis

Drug prophylaxis is not recommended. However, HIV patients should generally be advised to pay attention to food hygiene , especially in warmer countries.

References

Albrecht H, Stellbrink HJ, Fenske S, Steiner P, Greten H. Salmonella typhimurium lung abscesses in an HIV-infected patient: successful treatment with oral ciprofloxacin. AIDS 1992, 6:1400-1.

Burckhardt B, Sendi P, Pfluger D, et al. Rare AIDS-defining diseases in the Swiss HIV Cohort Study. Eur J Clin Microbiol Infect Dis 1999, 18:399-402.

Forrest GN, Wagner LA, Talwani R, Gilliam BL. Lack of fluoroquinolone resistance in non-typhoidal salmonella bacteremia in HIV-infected patients in an urban US setting. J Int Assoc Physicians AIDS Care 2009, 8:338-41.

Gordon MA. Salmonella infections in immunocompromised adults. J Infect 2008, 56:413-22.

Hung CC, Hsieh SM, Hsiao CF, Chen MY, Sheng WH. Risk of recurrent non-typhoid Salmonella bacteraemia after early discontinuation of ciprofloxacin as secondary prophylaxis in AIDS patients in the era of HAART. AIDS 2001, 15:645-7.

Hung CC, Hung MN, Hsueh PR, et al. Risk of recurrent nontyphoid Salmonella bacteremia in HIV-infected patients in the era of highly active antiretroviral therapy and an increasing trend of fluoroquinolone resistance. Clin Infect Dis 2007;45.

Jacobs JL, Gold JW, Murray HW, Roberts RB, Armstrong D. Salmonella infections in patients with the AIDS. Ann Intern Med 1985, 102:186-8.

Jacobson MA, Hahn SM, Gerberding JL, et al. Ciprofloxacin for Salmonella bacteremia in the AIDS. Ann Intern Med 1989, 110:1027–1029.

Kitkungvan D, Apisarnthanarak A, Plengpart P, Mundy LM. Fever of unknown origin in patients with HIV infection in Thailand: an observational study and review of the literature. Int J STD AIDS 2008, 19:232-5.

MacLennan CA, Gilchrist JJ, Gordon MA, et al. Dysregulated humoral immunity to nontyphoidal Salmonella in HIV-infected African adults. Science 2010, 328:508-12.

Nadelman RB, Mathur-Wagh U, Yancovitz SR, Mildvan D. Salmonella bacteremia associated with the AIDS. Arch Intern Med 1985, 145:1968-71.

Nelson MR, Shanson DC, Hawkins DA, Gazzard BG. Salmonella, Campylobacter and Shigella in HIV-seropositive patients. AIDS 1992, 6:1495-8.

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Filed under 11. Opportunistic Infections, Part 3 - AIDS, Salmonella septicemia

Immune reconstitution inflammatory syndrome (IRIS)

– Christian Hoffmann –

For the first time, in mid-1997 and early 1998, two groups described atypical manifestations of CMV retinitis (Jacobsen 1997) and MAC disease with abscess formation (Race 1998) in HIV patients within a few weeks of initiation of ART. Although the pathogens, pathogenesis and localization were very different, all these illnesses had a distinct inflammatory component and were associated with significant immune reconstitution in these patients. Consequently, suspected early on that these presentations could constitute a syndrome during which a latent infection present at initiation of therapy is fought more effectively by the recovering immune system (Overview: French 2009). Infections are not the only cause of an IRIS. Malignancies and other diseases have also been decribed as IRIS-related (see below).

The International Network for the Study of HIV-associated IRIS (INSHI, http://www.med.umn.edu/inshi/) has established the following consensus criteria for diagnosis of IRIS:

1. Response to ART (at least one log10 copies/mL decrease in HIV RNA)

2. Clinical deterioration of an infectious or inflammatory condition temporally related to ART initiation.

3. Symptoms cannot be explained by expected clinical course of a previously recognized and successfully treated infection, medication side effect or toxicity, treatment failure or complete non-adherence.

One must differentiate between subclinical infections first appearing on ART (“unmasking IRIS”) and clinically evident infections already existing at therapy initiation, which often paradoxically become worse during therapy (”paradoxical IRIS”).

IRIS in many publications today is often a collection of bizarre, sometimes grotesque case reports, which have actually only one common ground: an unexpected, usually clinically impressing infection, differing significantly from the courses of diseases seen during the pre-HAART era. Nevertheless, IRIS has three rules:

  1. Anything is possible.
  2. Nothing is as it was in the pre-HAART era.
  3. IRIS does not mean that ART has failed. In addition, the patients usually have a good prognosis.

How frequently does IRIS occur? Due to the lack of a definition in the early years of ART, the data vary substantially. In our experience, a frequency of 5-10% in patients with less than 200 CD4 T cells/µl is realistic. Very low CD4 T cells, a high viral load before initiation of therapy or a rapid drop of HIV RNA on ART seem to be important predictive factors for IRIS. If one focus on the patients who were already infected with mycobacteria or cryptococcus neoformans before ART was started, IRIS rates of 30% are reached (Müller 2010).

Mycobacterial IRIS. For MAC, the number of published cases with grotesque, fistular lymphadenitis, cutaneous or muscular abscesses, osteomyelitis, nephritis or meningitis is too large to be cited here. After a total of 83 patients started ART with a CD4 T cell count of less than 200/µl, only six mycobacterioses, among these four MAC infections were observed within the first weeks of beginning therapy (Hoffmann 1999). Lymph node abscesses usually occur during the first weeks on ART. IRIS cases with Mycobacterium xenopi or kansasii have also been described (Chen 2004, Phillips 2005).

There are now also numerous reports on tuberculosis (John 1998, Chien 1998), which are reminiscent of the “paradox” reactions to TB treatment known since the 1950s. All of these patients similarly suffered an initial deterioration under sufficient tuberculostatic treatment and ART-induced immune reconstitution. By the same token, meningitis as well as marked lymphadenopathy with unspecific histology can complicate the course of disease, yet both respond astonishingly rapidly and well to steroids. Prednisolone was very effective in a recent placebo-controlled trial (Meintjes 2010).

It is still not clear whether an early or immediate start of ART in therapy naïve patients facilitates the occurrance of an IRIS. In at least two large randomized trials (STIDE and SAPIT) the risk of an IRIS increased when ART was started immediately in patients with TB. In both studies, however, the increased risk did not lead to an increased mortality (Abdool 2011, Havlir 2011). A randomized study in patients with tuberculous meningitis contradicts these results showing less favorable effects for an early ART (Torok 2009).

CMV IRIS. In addition to mycobacteriosis, numerous cases of unusual CMV infections under ART have been published. In patients with previously diagnosed CMV retiniotis, IRIS developed in 38% (Müller 2010). Inflammatory CMV retinitis with vitritis that may lead to visual impairment, papillitis and macular edema, can now be described as a distinct syndrome, differing significantly from the course of CMV retinitis seen in the pre-HAART era (Jacobson 1997, Karavellas 1999). Neovascularization endangers vision even after resolution (Wright 2003). As with MAC disease, in vitro studies have shown that the CMV-specific immune response is improved most significantly in those patients developing vitritis (Mutimer 2002, Stone 2002). Inflammatory CMV manifestations are not limited to the retina and may involve other organs.

PML IRIS. The course of inflammatory PML that occurs during an IRIS is different from the infaust prognosis seen during the pre-HAART era (Collazos 1999, Kotecha 1998, Cinque 2001, Miralles 2001). Clinical symptoms are often more fulminant initially, and on radiology, there is a contrast enhancement which is otherwise atypical for PML, that may resolve over time. Patients have a better prognosis, and PML seems to even resolve completely (Hoffmann 2003, Du Pasquier 2003). It appears that a number of patients with inflammatory PML, who have been asymptomatic for years, live without any residual symptoms. However, fatal cases of inflammatory PML have also been reported (Safdar 2002). Previously documented experiences indicate that steroids are ineffective, although there have been accounts of positive results (Nuttall 2004, Tan 2009).

Cryptococcal IRIS. Numerous cases with inflammatory courses of disease have been described (Overview: Haddow 2010). Together with MAC/TBC and CMV, cryptococci are probably the most influential pathogens that contribute to an IRIS. In particular, severely immunocompromised patients who start with ART after cryptococcal therapy should be watched closely for the first few weeks and months. Newer studies show that 10-20% of patients with co-infections develop a cryptococcal IRIS (Sungkanuparph 2009, Müller 2010). The MRI usually shows choriomeningitis with significant enhancement in the choroid plexus. Cryptococcal antigen in the CSF is positive, although culture remains negative (Boelaert 2004). The intracranial pressure is often particularly high (Shelbourne 2005). As well as meningitis, lymphadenitis can also occur (Skiest 2005).

IRIS, induced by other infections. A variety of contemporary case studies have documented the induction of IRIS by the following infections: leishmaniasis (Jiménez-Expósito 1999), penicillosis (Ho 2010), histoplasmosis (De Lavaissiere 2008), pneumocystosis (Barry 2002, Koval 2002, Godoy 2008, Jagannathan 2009, Mori 2009), or herpes (Fox 1999). Herpes zoster and hepatitis B or C episodes also seem to occur on ART, particularly during the first weeks (Behrens 2000, Chung 2002, Manegold 2001, Martinez 1998, Domingo 2001). HHV-8-associated Kaposi’s sarcoma can worsen significantly on ART in the presence of an IRIS (Bower 2005, Leidner 2005, Feller 2008). Increasing dermatological problems such as exacerbation of pre-existing folliculitis or skin disease have also been reported (Handa 2001, Lehloenyia 2006, Pereira 2007, Iarikov 2008). There are even reports about parvovirus and leprosy (Nolan 2003, Couppie 2004, Bussone 2010, Watanabe 2011).

IRIS and other diseases. Diseases other than OIs are now recognized to occur under IRIS. These include autoimmune diseases such as Graves’ disease, lupus, Sweet’s and Reiter’s syndromes, Guillain-Barré syndrome, acute porphyria, gout and sarcoidosis, to name but a few (Bevilacqua 1999, Behrens 1998, Fox 1999, Gilquin 1998, Makela 2002, Mirmirani 1999, Neumann 2003, Piliero 2003, Sebeny 2010). Even two cases of Peyronie’s disease, a fibrosis of the penis, were reported (Rogers 2004). These reports do raise the question of whether all of these manifestations are truly induced by immune reconstitution or perhaps merely chance occurrences. While most reports initially offered little information on the etiology beyond purely hypothetical discussions, it has recently become apparent that changes in the cytokine profile are involved in the pathogenesis of IRIS, together with an activation of the cellular immune response. However, it seems that the mechanisms differ according to disease and genetic profile (Price 2001, Shelbourne 2005).

Consequences

Patients starting ART with less than 200 CD4 T cells/µl and particularly those who have a high viral load require close clinical monitoring during the first weeks. Close attention should be give especially in cases where very immunocompromised patients who have previously declined antiretroviral treatment, suddenly feel physically “affected,” express subfebrile conditions, and want to start ART “after thinking about it for a long time.” Latent infections are often present in such cases and rapidly become apparent as immune reconstitution occurs – the poorer the immune status and the longer its duration, the greater the danger of IRIS. Although newer studies prove that infection parameters such as CROP, D-dimer or cytokines such as IL-6 or IP-7 are predictive for an IRIS or OI (Rodger 2009, Antonelli 2010, Porter 2010) it is not generally practiced in routine diagnosis.

However chest radiography, abdominal ultrasound and fundoscopy should be included in routine investigations of such patients before beginning treatment. Moreover, clinical examination which nowadays are often gladly overlooked should be taken seriously. Some authors suggest that MAC prophylaxis start even before ART in severely immunocompromised patients seems problematic, even though prophylaxis cannot prevent MAC IRIS (Phillips 2002+2005). Still, prospective clinical studies have yet to prove whether administration of IL-2 or GM-CSF is worthwhile, as was recently postulated (Pires 2005).

Mycobacterioses in particular should be treated generously with steroids. This has been confirmed in a randomized trial (Meintjes 2010). One should always be prepared for atypical localizations, findings and disease courses of opportunistic infections. Generally speaking, prognosis of IRIS usually is good. Mortality of patients developing IRIS is reportedly not higher than that of patients without IRIS (Park 2006).

References

Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with HIV receiving HAART. Clin Infect Dis 2002, 35:E8-E13.

Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010, 362:697-706.

Aberg JA, Chin-Hong PV, McCutchan A, et al. Localized osteomyelitis due to Mycobacterium avium complex in patients with HIV receiving HAART. Clin Infect Dis 2002, 35:E8-E13.

Antonelli L, Yolanda Mahnke Y, Hodge J, et al. Elevated serum IL-7 levels, expansion of memory CD4+ T cells, augmented t cell activation and inflammation in patients developing IRIS after ART initiation. Abstract 336, 17th CROI 2010, San Francisco.

Barry SM, Lipman MC, Deery AR, Johnson MA, Janossy G. Immune reconstitution pneumonitis following Pneumocystis carinii pneumonia in HIV-infected subjects. HIV Med 2002, 3:207-11.

Behrens G, Knuth C, Schedel I, Mendila M, Schmidt RE. Flare of SLE following HAART. Lancet 1998, 351:1057-8.

Behrens GM, Meyer D, Stoll M, Schmidt RE. Immune reconstitution syndromes in HIV infection following effective antiretroviral therapy. Immunobiology 2000, 202:186-93.

Bevilacqua S, Hermans P, Van Laethem Y, Demaubeuge J, Clumeck N. Sweet’s syndrome in an HIV-infected patient. AIDS 1999, 13: 728-9.

Boelaert JR, Goddeeris KH, Vanopdenbosch LJ, Casselman JW. Relapsing meningitis caused by persistent cryptococcal antigens and immune reconstitution after the initiation of highly active antiretroviral therapy. AIDS 2004, 18:1223-4.

Bower M, Nelson M, Young AM, et al. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. J Clin Oncol 2005, 23:5224-8.

Bussone G, Charlier C, Bille E, et al. Unmasking leprosy: an unusual immune reconstitution inflammatory syndrome in a patient infected with human immunodeficiency virus. Am J Trop Med Hyg 2010, 83:13-4.

Chen F, Sethi G, Goldin R, Wright AR, Lacey CJ. Concurrent granulomatous Pneumocystis carinii and Mycobacterium xenopi pneumonia: an unusual manifestation of HIV immune reconstitution disease. Thorax 2004, 59:997-999.

Chien JW, Johnson JL. Paradoxical reactions in HIV and pulmonary TB. Chest 1998, 114: 933-6.

Chung RT, Evans SR, Yang Y, et al. Immune recovery is associated with persistent rise in HCV RNA, infrequent liver test flares, and is not impaired by HCV in co-infected subjects. AIDS 2002, 16:1915-1923.

Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001, 7:358-63.

Collazos J, Mayo J, Martinez E, Blanco MS. Contrast-enhancing progressive multifocal leukoencephalopathy as an immune reconstitution event in AIDS patients. AIDS 1999, 13: 1426-1428.

Couppie P, Abel S, Voinchet H, et al. Immune reconstitution inflammatory syndrome associated with HIV and leprosy. Arch Dermatol. 2004, 140:997-1000.

De Lavaissière M, Manceron V, Bourée P, et al. Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection. J Infect 2008 Dec 16. [Epub ahead of print]

Domingo P, Torres OH, Ris J, Vazquez G. Herpes zoster as an immune reconstitution disease after initiation of combination antiretroviral therapy in patients with HIV-1 infection. Am J Med 2001, 110:605-9.

Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003, 9 Suppl 1:25-31.

Feller L, Anagnostopoulos C, Wood NH, et al. Human immunodeficiency virus-associated Kaposi sarcoma as an immune reconstitution inflammatory syndrome: a literature review and case report. J Periodontol 2008;79:362-8.

Fox PA, Barton SE, Francis N, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Med 1999, 1:10-8.

Fox PA, Boag FC, Hawkins DA, Francis N. Acute porphyria following commencement of indinavir. AIDS 1999, 13: 622-3.

French MA, Lenzo N, John M, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with HAART. HIV Med 2000, 1:107-15.

French MA. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin Infect Dis 2009, 48:101-7.

Ghosn J, Paris L, Ajzenberg D, et al. Atypical toxoplasmic manifestation after discontinuation of maintenance therapy in a HIV type 1-infected patient with immune recovery. Clin Infect Dis 2003; 37: E112-4.

Gilquin J, Viard JP, Jubault V, Sert C, Kazatchkine MD. Delayed occurrence of Graves’ disease after immune restoration with HAART. Lancet 1998, 352:1907-8.

Godoy MC, Silva CI, Ellis J, Phillips P, Muller NL. Organizing pneumonia as a manifestation of Pneumocystis jiroveci immune reconstitution syndrome in HIV-positive patients: report of 2 cases. J Thorac Imaging 2008;23:39-43.

Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010, 10:791-802.

Haddow LJ, Easterbrook PJ, Mosam A, et al.  Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis 2009, 49:1424-32.

Handa S, Bingham JS. Dermatological immune restoration syndrome: does it exist? J Eur Acad Dermatol Venereol 2001, 15:430-2.

Havlir D, Ive P, Kendall M, et al. International Randomized Trial of Immediate vs Early ART in HIV+ Patients Treated for TB: ACTG 5221 STRIDE Study. Abstract 38, 18th CROI 2011, Boston.

Ho A, Shankland GS, Seaton RA. Penicillium marneffei infection presenting as an immune reconstitution inflammatory syndrome in an HIV patient. Int J STD AIDS 2010, 21:780-2.

Hoffmann C, Degen O, Horst HA, van Lunzen J, Stellbrink HJ. Immune reconstitution in severely immunocompromised patients initiating HAART – the critical first months. 7. Deutscher AIDS-Kongress 1999, Essen, F1088.

Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003, 74:1142-4.

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Karavellas MP, Plummer DJ, Macdonald JC, et al. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful HAART. J Infect Dis 1999, 179: 697-700.

Koval CE, Gigliotti F, Nevins D, Demeter LM. Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with HIV type 1 infection. Clin Infect Dis 2002, 35:491-3.

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Mirmirani P, Maurer TA, Herndier B, et al. Sarcoidosis in a patient with AIDS: a manifestation of immune restoration syndrome. J Am Acad Dermatol 1999, 41:285-6.

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Mutimer HP, Akatsuka Y, Manley T, et al. association between immune recovery uveitis and a diverse intraocular cytomegalovirus-specific cytotoxic T cell response. J Infect Dis 2002, 186: 701-5.

Neumann S, Kreth F, Schubert S, Mossner J, Caca K. Reiter’s syndrome as a manifestation of an immune reconstitution syndrome in an hiv-infected patient: successful treatment with doxycycline. Clin Infect Dis 2003; 36: 1628-9.

Nolan RC, Chidlow G, French MA. Parvovirus b19 encephalitis presenting as immune restoration disease after highly active antiretroviral therapy for HIV infection. Clin Infect Dis 2003; 36: 1191-4.

Nuttall JJ, Wilmshurst JM, Ndondo AP, et al. Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced HIV infection: a case of immune reconstitution inflammatory syndrome. Pediatr Infect Dis J 2004, 23:683-5.

Park WB, Choe PG, Jo JH, et al. Immune reconstitution inflammatory syndrome in the first year after HAART: influence on long-term clinical outcome. AIDS 2006, 20:2390-2.

Pereira B, Fernandes C, Nachiambo E, et al. Exuberant molluscum contagiosum as a manifestation of the immune reconstitution inflammatory syndrome. Dermatol Online J 2007;13:6.

Phillips P, Bonner S, Gataric N, et al. Nontuberculous mycobacterial immune reconstitution syndrome in HIV-infected patients: spectrum of disease and long-term follow-up. Clin Infect Dis 2005, 41:1483-97.

Phillips P, Chan K, Hogg R, et al. Azithromycin prophylaxis for Mycobacterium avium complex during the era of HAART: evaluation of a provincial program. Clin Infect Dis 2002, 34: 371-8.

Piliero PJ, Fish DG, Preston S, et al. Guillain-Barre syndrome associated with immune reconstitution. Clin Infect Dis 2003; 36:e111-4.

Pires A, Nelson M, Pozniak AL, et al. Mycobacterial immune reconstitution inflammatory syndrome in HIV-1 infection after antiretroviral therapy is associated with deregulated specific T-cell responses: beneficial effect of IL-2 and GM-CSF immunotherapy. J Immune Based Ther Vaccines 2005, 3:7.

Porter BO, Ouedraogo GL, Hodge JN, et al. d-Dimer and CRP levels are elevated prior to antiretroviral treatment in patients who develop IRIS. Clin Immunol 2010, 136:42-50.

Price P, Mathiot N, Krueger R, Stone S, Keane NM, French MA. Immune dysfunction and immune restoration disease in HIV patients given HAART. J Clin Virol 2001, 22:279-87.

Race EM, Adelson-Mitty J, Kriegel GR, et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet 1998, 351:252-5.

Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis 2009, 200:973-83.

Rogers GD, French MA. Peyronie’s disease in men with HIV responding to highly active antiretroviral therapy. HIV Med 2004, 5:185-6.

Safdar A, Rubocki RJ, Horvath JA, et al. Fatal immune restoration disease in HIV type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002; 35: 1250-7.

Sebeny PJ, Keith MP, Love KM, Dwyer TX, Ganesan A. Refractory polyarticular gouty arthritis as a manifestation of immune reconstitution inflammatory syndrome. J Clin Rheumatol 2010, 16:40-2.

Shelburne SA, Visnegarwala F, Darcourt J, et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 2005, 19:399-406.

Skiest DJ, Hester LJ, Hardy RD. Cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. J Infect. 2005, 51:e289-97.

Stone SF, Price P, Tay-Kearney ML, French MA. Cytomegalovirus (CMV) retinitis immune restoration disease occurs during HAART-induced restoration of CMV-specific immune responses within a predominant Th2 cytokine environment. J Infect Dis 2002, 185:1813-7.

Stout JE, Lai JC, Giner J, Hamilton CD. Reactivation of retinal toxoplasmosis despite evidence of immune response to highly active antiretroviral therapy. Clin Infect Dis 2002; 35:E37-9.

Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter  study. Clin Infect Dis 2009, 49:931-4.

Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009, 72:1458-64.

Torok ME, Yen NTB, Chau TTH, et al. Randomised controlled trial of immediate versus deferred antiretroviral therapy in HIV-associated tuberculosis meningitis. Abstract H-1224, 49th ICAAC 2009, San Francisco.

Tsambiras PE, Larkin JA, Houston SH. Toxoplasma encephalitis after initiation of HAART. AIDS Read 2001, 11:608-10.

Watanabe D, Taniguchi T, Otani N, et al. Immune reconstitution to parvovirus B19 and resolution of anemia in a patient treated with highly active antiretroviral therapy. J Infect Chemother 2011, 17:283-7.

Wright ME, Suzman DL, Csaky KG, Extensive retinal neovascularization as a late finding in human immunodeficiency virus-infected patients with immune recovery uveitis. Clin Infect Dis 2003;36:1063-6.

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Filed under 11. Opportunistic Infections, Immune reconstitution inflammatory syndrome (IRIS), Part 3 - AIDS

Wasting syndrome

– Christian Hoffmann –

Wasting syndrome is defined as involuntary weight loss of at least 10% of original body weight accompanied by persistent diarrhea (at least two bowel movements daily for more than 30 days) or extreme fatigue and/or fever without apparent infectious etiology. With thorough and competent searching, a specific causative agent can usually be found for wasting syndrome because it is essentially a classical exclusion diagnosis and really more of an epidemiological instrument than a specific disease. Although previously a very frequent condition, wasting syndrome has become rare today. For example, in a large study conducted in 2000, only 14% of patients still indicated having lost more than 10% of their original body weight (Wanke 2000). Rates are even higher in intravenous drug users (Campa 2005). Weight loss remains an independent risk factor for mortality, even in the HAART era, and every patient should be weighed regularly. In one large study, mortality risk in patients with a loss greater than 10% of body weight was more than four to six times higher than that of patients with stable body weight (Tang 2002). Patients with classic wasting syndrome are often extremely weak. That said, the risk for opportunistic infections is significantly elevated (Dworkin 2003). There is also cognitive impairment in these patients (Dolan 2003).

Diagnosis

The causes of wasting syndrome are complex. First, it is necessary to exclude or treat opportunistic infections (TB, MAC, cryptosporidiosis and microsporidiosis). If none are found, then several reasons remain that may contribute, even in combination, to wasting syndrome. These include:  metabolic disorders, hypogonadism, poor nutrition and malabsorption syndromes (overview: Grinspoon 2003).

Consequently, a thorough patient history is extremely beneficial. Does the patient have a sensible diet? How are meals distributed throughout the day? Is the patient depressed? Which drugs (ART) are being taken? Distinction from antiretroviral-induced lipoatrophy (d4T/ ddI) is often difficult. Significant weight loss also occurs frequently on interferon (Garcia-Benayas 2002), but rapidly resolves after finishing treatment. In addition, hypogonadism should be ruled out with the measurement of testosterone. While there are several simple tests for malabsorption syndromes, it is prudent to start with testing albumin as well as TSH and cholesterol levels.

Further tests such as D-xylose absorption or biopsies of the small intestine should only be initiated after consulting with a gastroenterologist. Other tests, such as DEXA, densitrometry, bioelectrical impedance analysis, should be conducted in centers experienced with wasting syndrome in AIDS patients to determine the patients’ body composition.

Therapy

Wasting syndrome always requires competent diet counseling. Exercise, if possible, is also good. Of course, both only have limited success. Supportive parenteral nutrition only helps if there are problems with absorption (Kotler 1990, Melchior 1996). Effective ART, ideally without drugs that cause lipoatrophy such as d4T or ddI, and possibly even omitting nucleoside analogs completely, is ideal. Severe lipoatrophy may require complete omission of nucleoside analogs (see chapter on Nuke sparing).

Beyond this, many kinds of drug treatment have been attempted. However, these have limited success and are often problematic.

Megestrol acetate, a synthetic gestagenic hormone, shows some benefit as an appetite stimulant in wasting syndrome, as demonstrated in some studies (Von Roenn 1994, Mulligan 2006). Its side effects are ones typically associated with steroids, including induced hypogonadism which should always be evaded, especially in cases of wasting syndrome. As a result, it is not widely nor currently recommended that this drug be used.

Dronabinol, the main active ingredient in marijuana, has been licensed in the US since 1985 as Marinol®, and may be prescribed for pharmacy formulation as drops or hard gel capsules. This drug is certainly attractive for many patients and sometimes actively demanded. Prescription should be carefully considered, particularly in view of the significant cost associated with the medication.  In some European countries, dronabinol costs approximately 600 Euros per month for the usual dose of 5 mg tid. Without a clear diagnosis of wasting syndrome, clarity about the health insurance coverage and communication with the insurance company may minimize substantial problems. In generally, some health insurances reject the request. The effect on wasting syndrome is moderate at best, if detectable at all (Beal 1995). It tends to be even weaker than megestrol acetate (Timpone 1997).

Hypogonadism, a frequent condition of patients with wasting syndrome, calls for the measurement of testosterone age-dependent levels. If the levels are low, then testosterone substitution has proven itself  as useful, both for weight gain and quality of life (Grinspoon 1998). A dose of 250 mg testosterone is given i.m. every 3-4 weeks, and there is a variety of less expensive generic names. The effect is sustained, even with long-term use (Grinspoon 1999). If testosterone levels are normal, then the substitution in cases of wasting syndrome is not indicated. In women, one should exercise caution when administering androgenic hormones. Other anabolic steroids are available in addition to testosterone, such as oxandrolone or nandrolone (Gold 2006, Sardar 2010). Although possibly more effective than testosterone, these drugs are commonly associated with other side effects, particularly those related to the liver (Corcoran 1999). Positive effects have been demonstrated with the anabolic steroid oxymetholone in a small, double-blind, randomized study (Hengge 2003). However, extremely high elevation of transaminases have been observed.

High costs and side effects have limited the use of recombinant human growth hormones (rhGH), for which long-term data is still not available (Mulligan 1993, Schambelan 1996). However, the results of a recent metaanalysis suggest that growth hormones may be more effective than anabolic steroids or testosterone in wasting syndrome (Moyle 2004). Common adverse events with rhGH therapy include blood glucose elevations, arthralgia, myalgia, and peripheral edema, but these usually respond to dose reduction or drug discontinuation (review: Gelato 2007).

References

Beal JE, Olson R, Laubenstein L, et al. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10:89-97.

Corcoran C, Grinspoon S. Treatments for wasting in patients with the acquired immunodeficiency syndrome. NEJM 1999, 340:1740-50.

Dolan S, Montagno A, Wilkie S, et al. Neurocognitive Function in HIV-Infected Patients With Low Weight and Weight Loss. J AIDS 2003; 34: 155-64.

Dworkin MS, Williamson JM. AIDS wasting syndrome: trends, influence on opportunistic infections, and survival. J AIDS 2003; 33: 267-73.

Garcia-Benayas T, Blanco F, Soriano V. Weight loss in HIV-infected patients. N Engl J Med 2002, 347: 1287-8.

Gelato M, McNurlan M, Freedland E. Role of recombinant human growth hormone in HIV-associated wasting and cachexia: pathophysiology and rationale for treatment. Clin Ther 2007;29:2269-88.

Gold J, Batterham MJ, Rekers H, et al. Effects of nandrolone decanoate compared with placebo or testosterone on HIV-associated wasting. HIV Med 2006, 7:146-55.

Grinspoon S, Corcoran C, Anderson E, Hubbard J, Basgoz N, Klibanski A. Sustained anabolic effects of long-term androgen administration in men with AIDS wasting. Clin Infect Dis 1999, 28:634-636.

Grinspoon S, Corcoran C, Askari H, et al. Effects of androgen administration in men with the AIDS wasting syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;129:18-26.

Grinspoon S, Mulligan K. Weight loss and wasting in patients infected with human immunodeficiency virus. Clin Infect Dis 2003; 36: S69-78.

Hengge UR, Stocks K, Faulkner S, et al. Oxymetholone for the treatment of HIV-wasting: a double-blind, randomized, placebo-controlled phase III trial in eugonadal men and women. HIV Clin Trials 2003; 4:150-63.

Kotler DP, Tierney AR, Culpepper-Morgan JA, Wang J, Pierson RN Jr. Effect of home total parenteral nutrition on body composition in patients with AIDS. J Parenter Enteral Nutr 1990;14:454-458.

Melchior J, Chastang C, Gelas P, et al. Efficacy of 2-month total parenteral nutrition in AIDS patients: a controlled randomized prospective trial. AIDS 1996;10:379-384.

Mulligan K, Grunfeld C, Hellerstein MK, et al. Anabolic effects of recombinant human growth hormone in patients with wasting associated with HIV infection. J Clin Endocrinol Metab 1993, 77:956-962.

Mulligan K, Zackin R, Von Roenn JH, et al. Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with hiv-associated weight loss: A randomized, double-blind, placebo-controlled multicenter trial. J Clin Endocrinol Metab 2006 Nov 7;

Sardar P, Jha A, Roy D, Majumdar U, et al. Therapeutic effects of nandrolone and testosterone in adult male HIV patients with AIDS wasting syndrome (AWS): a randomized, double-blind, placebo-controlled trial. HIV Clin Trials 2010, 11:220-9.

Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting: a randomized, placebo-controlled trial. Ann Intern Med 1996, 125:873-882.

Tang AM, Forrester J, Spiegelman D, et al. Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. J AIDS 2002, 31: 230-6.

Timpone JG, Wright DJ, Li N, et al. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. AIDS Res Hum Retroviruses 1997, 13:305-15.

Von Roenn JH, Armstrong D, Kotler DP, et al. Megesterol acetate in patients with AIDS-related cachexia. Ann Intern Med 1994, 121:393-399.

Wanke CA, Silva M, Knox TA, et al. Weight loss and wasting remain common complications in individuals infected with HIV in the era of highly active antiretroviral therapy. Clin Infect Dis 2000, 31:803-5.

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Filed under 11. Opportunistic Infections, Part 3 - AIDS, Wasting syndrome

Rare OIs

– Christian Hoffmann and Gerd Fätkenheuer –

Several opportunistic infections that rarely occur in central Europe or have become increasing rare due to the introduction of ART include: aspergillosis, bacillary angiomatosis, histoplasmosis, isosporiasis, coccidioidomycosis (Coccidioides immitis), visceral leishmaniasis, microsporidiosis, Penicillium marneffei mycosis, and rhodococcosis. In addition to affecting HIV-infected patients more frequently than immunocompetent individuals, these infections also are considered to have more severe courses of disease and more frequent recurrences in HIV-infected patients than in HIV-negative patients. Despite this, according to the current CDC/WHO classification, only histoplasmosis, isosporiasis, and coccidioidomycosis are AIDS-defining.

Aspergillosis

Aspergillosis occurs almost exclusively in severely immunocompromised patients but is not classified as AIDS-defining. In the largest series described worldwide to date, in a study of 342  cases of invasive aspergillosis, almost all of the patients had less than 50 CD4 T cells/µl (Mylonakis 1998). Although the lungs are largely susceptible to pneumonia or tracheobronchitis, almost all other organs can be compromised, particularly the CNS. Sinusitis or abcesses in kidney or liver are other manifestations (Hunt 2000, Myolonakis 2000)

For the most part, aspergillosis occurs in HIV patients on long-term and in some cases excessively long steroid treatment for another OI. Severe neutropenia (< 1,000 leucocytes) is another risk factor. Found in over 90% of invasive aspergillosis cases, Aspergillus fumigatus is by far the most frequent pathogen. Other important aspergillus pathogens are A. flavus, A. niger, A. terreus, and A. nidulans. The severely ill patients complain of fever, cough, dyspnea and chest pain. Hemoptysis frequently occurs.

The only way to reach a reliable diagnosis is biopsy. A serum antigen test on Galactomannan, a component of the cell wall of Aspergillus (not exclusively, also other mycoses) may support the diagnosis. Chest x-rays often remain inconspicuous. In the HR-CT, bilateral, multifocal and nodular lesion could be the most common radiological characteristic, while Halo and crescentic sign occur occasionally.

Treatment should be initiated immediately. Suspicion of aspergillosis justifies a treatment attempt without definitive diagnosis i.e., biopsy results. Each delay worsens a potentially unfavorable prognosis substantially. At present voriconazole is considered as to be treatment of choice (Schwartz 2005). In contrast to other antifungal drugs, voriconazole penetrates well into the CNS. In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B (Herbrecht 2002). Voriconazol is given at a dosage of 4 mg i.v./kg BID (Loading dose: 6 mg/kg BID on day 1, oral therapy with 200 mg BID starting from day 7). Main adverse events are visual disturbances (20%) and (reversible) increases of liver enzymes.

An alternative approach is Amphotericin B, whose inferiority to voriconazole is doubted by some authors (Jorgensen 2006). The effect of combinations is not proven. Salvage therapy include lipid-based formulations of amphotericin B, caspofungin, high-dose itraconazole, posaconazole and micafungin (Dockrell 2008). A systematic steroid therapy should be stopped if possible and every patient should receive antiretroviral treatment immediately. Some case reports describe that permanent therapy could be dropped if immune reconstitution was sufficient (Yoganathan 2009).

References

Umfassende Übersicht: Aspergillose – Stand des Wissens zu Diagnose, Therapie;

Dockrell DH. Salvage therapy for invasive aspergillosis. J Antimicrob Chemother 2008;61:Suppl 1.

Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002, 347:408-15.

Hoang A. Caspofungin acetate: an antifungal agent. Am J Health Syst Pharm 2001, 58:1206-14.

Hunt SM, Miyamoto RC, Cornelius RS, Tami TA. Invasive fungal sinusitis in the AIDS. Otolaryngol Clin North Am 2000, 33:335-47.

Jorgensen KJ, Gotzsche PC, Johansen HK. Voriconazole versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev 2006; 0.

Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 1998, 114:251-62.

Mylonakis E, Paliou M, Sax PE, Skolnik PR, Baron MJ, Rich JD. Central nervous system aspergillosis in patients with HIV infection. Report of 6 cases and review. Medicine (Baltimore) 2000, 79:269-80.

Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005, 106:2641-5.

Yoganathan K. Long-term suppressive therapy for pulmonary aspergilloma in an immunocompromised man with AIDS. Is it always necessary? Int J STD AIDS 2009, 20:434-6.

Bacillary angiomatosis

Bacillary angiomatosis in HIV patients was first described in the 1980’s (Review: Maguina 2000). Bacillary angiomatosis is caused by the rickettsial species Bartonella henselae and Bartonella quintana (“Rochalimaea” until the beginning of the 1990’s). While Bartonella henselae is typically associated with cats, its primary host, and cat fleas, its vector; Bartonella quintana frequently affects homeless patients and is associated with poor hygiene and social-economic conditions. Several possible reservoirs have been discussed for such cases (Gasquet 1998). In a Spanish study of 340 HIV-infected patients, 22% patients reacted to one or more Bartonella antigens. Of all the studied seroprevalence rate factors, only age was statistically significant (Pons 2008). Reportedly, Bartonella occurs more often in North and South America than in Europe. In Brasil, the seroprevalence was 38 % (Lamas 2010). In a study of 382 febrile HIV patients in San Francisco, Bartonella was found to be the causative organism in 18% (Koehler 2003).

Bacillary angiomatosis remains an significant differential diagnosis in all cases with skin lesions of unknown etiology. The pseudoneoplastic, vascular skin proliferation is quite often clinically and histologically mistaken for Kaposi’s sarcoma or hemangioma. The vascular nodules or tumors may be isolated, but are usually multiple and reminiscent of fresh Kaposi’s sarcoma, with cherry red or purple nodules. One quarter of the cases may have bone involvement with painful osteolytic foci (AP elevation). Here, the skin lesions sometimes resemble dry hyperkeratotic changes such as those seen in psoriasis. Different organs may be affected. In a collection of 21 cases, 19 patients had skin, 5 bone and 4 liver involvement (Plettenberg 2000). Manifestations in lymph nodes, muscle, CNS, eye, gingiva and gastrointestinal tract have also been reported.

Diagnosis of BA is difficult. The gram-negative bacteria are only visible on biopsy samples stained with Warthin Starry silver stain. If this stain method is not applied, then bacillary angiomatosis will not be find.  Moreover, pathologists should be informed of the suspected diagnosis, as the Warthin Starry silver stain is not routinely performed. PCR is also possible. Reference laboratories should be contacted for further diagnostic details.

Treatment of bacillary angiomatosis is with erythromycin (at least four weeks with 500 mg qid) or clarithromycin. Relapses are common, which is why some physicians favor therapy for at least three months. Supposedly effective, doxycyclin, is the therapy of choice for CNS involvement. Since transmission is generally via cats, American guidelines recommend not having cats as pets. Preferably, cats should be healthy and older than one year; and scratches should be avoided.

References

Cockerell CJ, LeBoit PE. Bacillary angiomatosis: a newly characterized, pseudoneoplastic, infectious, cutaneous vascular disorder. J Am Acad Dermatol 1990, 22:501-12.

Gasquet S, Maurin M, Brouqui P, Lepidi H, Raoult D. Bacillary angiomatosis in immunocompromised patients. AIDS 1998, 12:1793-803.

Koehler JE, Sanchez MA, Garrido CS, et al. Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-peliosis. N Engl J Med 1997, 337:1876-83.

Koehler JE, Sanchez MA, Tye S, et al. Prevalence of Bartonella infection among hiv-infected patients with fever. Clin Infect Dis 2003, 37:559-66.

Lamas CC, Mares-Guia MA, Rozental T, et al. Bartonella spp. infection in HIV positive individuals, their pets and ectoparasites in Rio de Janeiro, Brazil: serological and molecular study. Acta Trop 2010, 115:137-41.

LeBoit PE, Berger TG, Egbert BM, Beckstead JH, Yen TSB, Stoler MH. Bacillary angiomatosis: the histopathology and differential diagnosis of a pseudoneoplastic infection in patients with HIV disease. Am J Surg Pathol 1989, 13:909-920.

Maguina C, Gotuzzo E. Bartonellosis. New and old. Infect Dis Clin North Am 2000, 14:1-22. Komplett im

Plettenberg A, Lorenzen T, Burtsche BT, et al. Bacillary angiomatosis in HIV-infected patients–an epidemiological and clinical study. Dermatology 2000, 201:326-31.

Pons I, Sanfeliu I, Nogueras MM, et al. Seroprevalence of Bartonella spp. infection in HIV patients in Catalonia, Spain. BMC Infect Dis 2008, 8:58.

Stoler MH, Bonfiglio TA, Steigbigel RB, et al: An atypical subcutaneous infection associated with AIDS. Am J Clin Pathol 1983, 80:714-718.

Histoplasmosis

Histoplasma capsulatum is a dimorphic mould, found largely in moist soil and without a capsule despite its name. The Southern and Midwestern of  regions of the US as well as Central America and Africa are endemic areas. Inhalation of microconidia, the spores of H. capsulatum, can cause granulomatous disease in the lungs of immunocompetent individuals. In HIV patients with impaired immunity (85% have less than 100 CD4 T cells/µl), infection leads to an acute, life-threatening disease with dry cough, fever, dyspnea and malaise (Gutierrez 2005, Mora 2008). Miliary TB and PCP are important differential diagnoses. Disseminated courses of disease may also occur, in which the fungus can be detected in bone marrow or by liver biopsy (Albrecht 1994). Skin ulcerations, oropharynx or CNS involvement may also occur (Scheinfeld 2003, Wheat 2005, Antonello 2011). Hepatosplenomegaly is common, occurring in almost 90% of the patients (Mora 2008).

Histoplasmosis is an AIDS-defining illness whose pathogen like that of cryptococcal antigen can be reliably detected in the blood with an antigen test. Laboratory evaluations often reveal significantly elevated LDH and alkaline phosphatase as well as transaminases.

Amphotericin B should be given as initial treatment. Liposomal amphotericin B (3 mg/kg daily for 14 days) is not only less toxic, but possibly also more effective (Johnson 2002). In milder cases, itraconazole (200 mg bid or tid) is effective, and can also be used as a secondary prophylaxis. It is significantly more effective than fluconazole (Wheat 2002), but is associated with a high risk of interactions, particularly with ritonavir, but also with efavirenz (Crommentuyn 2004, Andrade 2009, Hills-Nieminen 2009). In such cases a modification of the doses is often necessary. With regard to other OIs, secondary prophylaxis for histoplasmosis can be discontinued if immune reconstitution is sufficient (Goldman 2004). Initiation of ART and the subsequent immune reconstitution may reveal undiagnosed latent disseminated histoplasmosis (Nacher 2006).

References

Albrecht H, Stellbrink HJ, Petersen J, et al. Disseminated histoplasmosis in AIDS. Dtsch Med Wschr 1994, 119:657-62.

Andrade RA, Evans RT, Hamill RJ, Zerai T, Giordano TP. Clinical evidence of interaction between itraconazole and nonnucleoside reverse transcriptase inhibitors in HIV-infected patients with disseminated histoplasmosis. Ann Pharmacother 2009, 43:908-13.

Antonello VS, Zaltron VF, Vial M, de Oliveira FM, Severo LC. Oropharyngeal histoplasmosis: report of eleven cases and review of the literature. Rev Soc Bras Med Trop. 2011, 1:26-9.

Crommentuyn KM, Mulder JW, Sparidans RW, et al. Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 2004, 38:e73-5.

Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004, 38:1485-9.

Gutierrez ME, Canton A, Sosa N, et al. Disseminated histoplasmosis in patients with AIDS in panama: a review of 104 cases. Clin Infect Dis 2005;40:1199-202.

Hills-Nieminen C, Hughes CA, Houston S, Shafran SD. Drug-drug interaction between itraconazole and the protease inhibitor lopinavir/ritonavir. Ann Pharmacother 2009, 43:2117-20.

Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002, 137: 105-9.

Mora DJ, dos Santos CT, Silva-Vergara ML. Disseminated histoplasmosis in AIDS patients in Uberaba, MG, Brazil. Mycoses 2008;51:136-40.

Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following HAART initiation. J AIDS 2006, 41:468-70.

Scheinfeld N. Diffuse ulcerations due to disseminated histoplasmosis in a patient with HIV. J Drugs Dermatol 2003, 2:189-91.

Wheat LJ, Connolly P, Haddad N, et al. Antigen clearance during treatment of disseminated histoplasmosis with itraconazole versus fluconazole in patients with AIDS. Antimicrob Agents Chemother 2002, 46:248-50.

Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Inf Dis 2005, 40:844-52.

Isosporiasis

Isospora belli is a ubiquitous intestinal parasite. While rare in Europe, it is a issue of great concern in the developing world, especially in the tropics and subtropics (Lagrange-Xelot 2008). In India Isospora belli was the most frequent diarrhea infection after cryptosporidiosis in HIV patients (Kulkarni 2009). Similar to cryptosporidiosis, this microbe may cause epidemic-type outbreaks in immunocompetent hosts. Patients suffer at a minimum with enteritis-like complaints and occasionally, also experience very severe watery diarrhea, abdominal pain, cramps and nausea.

In immunocompromised patients, chronic diarrhea and malnutrition may occur (review in: Goodgame 1996). Fever is seldom seen. CD 4 T-cell count in patients with Isoporiasis is 150/µ in the median and slightly higher than in cases of cryptosporidiosis and microsporidia.

Chronic isosporiasis with diarrhea lasting for more than four weeks is AIDS-defining. Detection of the relatively large oocysts is possible via normal stool sampling for parasites, as well as in acid-fast stains. Blood tests usually reveal eosinophilia (Certad 2003).

Treatment is co-trimoxazole (960 mg daily for one week). Ciprofloxacin is slightly less effective (Verdier 2000). Relapse is common despite cotrimoxazole maintenance therapy (Lagrange-Xelot 2008).

References

Certad G, Arenas-Pinto A, Pocaterra L, et al. Isosporiasis in Venezuelan adults infected with hiv: clinical characterization. Am J Trop Med Hyg 2003, 69:217-22.

Goodgame RW. Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, cyclospora. Ann Int Med 1996,124:429-41

Kulkarni SV, Kairon R, Sane SS, et al. Opportunistic parasitic infections in HIV/AIDS patients presenting with diarrhoea by the level of immunesuppression. Indian J Med Res 2009, 130:63-6.

Lagrange-Xelot M, Porcher R, Sarfati C, et al. Isosporiasis in patients with HIV infection in the HAART era in France. HIV Med 2008;9:126-30.

Verdier RI, Fitzgerald DW, Johnson WD Jr, Pape JW. Trimethoprim-sulfamethoxazole compared with ciprofloxacin for treatment and prophylaxis of Isospora belli and Cyclospora cayetanensis infection in HIV-infected patients. A randomized, controlled trial. Ann Intern Med 2000, 132:885-8.

Coccidioidomycosis

Infection with the mould Coccidioides immitis is endemic in the Southwestern US and therefore, taken into consideration when presented with patients who have been in this region. (review: Galgiani 2005, Ampel 2007). Laboratory personnel also should also be informed of the high risk of infection, even in suspected cases.

After inhalation of spores, the primary manifestation begins in the lungs (Pappagianis 1993). Approximately 1-3 weeks after exposure, a pneumonia-like illness develops with fever, cough, chest pain and general malaise. The infection, although often symptomatic, usually resolves in immunocompetent patients without sequelae. Occasionally, there is residual cavitation which in some cases require surgical intervention (Jaroszewski 2009). Disseminated coccidioidomycosis beyond the lung and hilar lymph nodes (for example chronic meningoencephalitis) occurs practically only in significantly immunocompromised patients with CD4 counts of less than 250 cells/µl (Ampel 2007, Drake 2009). Disseminated coccidioidomycosis is an AIDS-defining illness. Prognosis was poor in the pre-HAART era. In an analysis of 602 patients with disseminated coccidioidomycosis, mortality after one year was 63% (Jones 1995). With ART the course of this illness is mostly less severe (Massannat 2010).

Serology is not very helpful in immunodeficient patients. Diagnosis is mostly made by cultures or histological materials (Adam 2009). Due to high infection risks, laboratory staff should be informed when in doubt of coccidioidomycosis.

Amphotericin as well as azoles are effective (Hernandez 1997), and should be, if necessary, combined (Ampel 2007). Detailed recommendations for the different situations (meningeal or disseminated cases must be treated more intensively) can be found in the publication of Galgiani 2005. Fluconazole should be given as maintenance therapy at high doses (400 mg).

In the past few years, it seems that the disease has become rarer as a result of ART, and that maintenance therapy can be discontinued when CD4 cells are greater than 250/µl with only initial pulmonary involvement. However, lifelong treatment is still recommended for cases of meningeal involvement (Woods 2000, Galgiani 2005, Ampel 2007).

References

Adam RD, Elliott SP, Taljanovic MS. The spectrum and presentation of disseminated coccidioidomycosis. Am J Med 2009, 122:770-7.

Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci 2007;1111:336-42.

Drake KW, Adam RD. Coccidioidal meningitis and brain abscesses: analysis of 71 cases at a referral center. Neurology 2009, 73:1780-6.

Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005, 41:1217-23.

Hernandez JL, Echevarria S, Garcia-Valtuille A, Mazorra F, Salesa R. Atypical coccidioidomycosis in an AIDS patient successfully treated with fluconazole. Eur J Clin Microbiol Infect Dis 1997, 16:592-4.

Jaroszewski DE, Halabi WJ, Blair JE, et al. Surgery for pulmonary coccidioidomycosis: a 10-year experience. Ann Thorac Surg 2009, 88:1765-72.

Masannat FY, Ampel NM. Coccidioidomycosis in patients with HIV-1 infection in the era of potent antiretroviral therapy. Clin Infect Dis 2010, 50:1-7.

Pappagianis D. Coccidioidomycosis. Semin Dermatol 1993, 12:301-9.

Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in HIV-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis 2000, 181:1428-34.

Leishmaniasis (visceral)

Leishmaniasis is an infectious disease that is caused by 20 species pathogenic for humans belonging to the genus Leishmania, a protozoa that is transmitted by sand flies. One must differentiate between the cutaneous and the visceral forms of leishmaniasis (Kalar Azar), the manifestation form depends on the species (L.donovani,L.infantum, L. chagasi). According to WHO, there are 12 million people infected with leishmania worldwide; while approximately 350 million people who live in risk areas. With such numbers leishmaniasis is one of the most important parasitosis. In Europe, visceral leishmaniasis is common and countries around the Mediterranean Sea, such as Spain, Portugal, France and Italy are affected the most. The following link provides a global overview: http://www.who.int/leishmaniasis/leishmaniasis_maps/en/index.html.

Visceral leishmaniasis appear more frequently in HIV infected patients. In Spain, the majority of patients with visceral leishmaniasis are now HIV-infected (Pintado 2001). Although there is much in favor of it, leishmaniasis is still not an AIDS-defining illness.

A review of 15 cases in Germany showed that all HIV patients were significantly immunosuppressed (usually less than 100 CD4 T cells/µl). A few patients had not been in endemic areas for several years (Albrecht 1998). Bone marrow involvement is reflected by the almost obligatory pancytopenia, which may be particularly severe in HIV patients (Pintado 2001). Other symptoms include fever, hepatosplenomegaly, and mucocutaneous lesions. The diagnosis is usually made from bone marrow aspirate.

Treatment of visceral leishmaniasis is difficult (review: Olliaro 2005). Pentavalent antimony compounds such as sodium stibogluconate (Pentostam®) or or meglumine antimoniate (Glucantime®) have been used for about 60 years (dosage usually used: 20 mg/kg i.v. or i.m. daily for 28 days). However, these drugs are extremely toxic. Myalgia, arthralgia, cardiotoxicity and chemical pancreatitis often lead to discontinuation (Laguna 1999). Combination therapies are possibly more effective and allow shorter therapy (van Griensven 2010, Sundar 2011).

The German Association for Tropical Medicine still recommends liposomal amphotericin B (AmBisome®) as the treatment of choice (2-5 mg/kg daily). Classic amphotericin B is also effective (Lachaud 2009). The only orally bioavailable leishmaniasis drug and a promising new drug, due to its good tolerability and efficacy, is miltefosine (Impavido®), an alkylphosphocholine analog that was licensed in Germany in December 2004. Although, clarity is still needed as to how miltefosine inhibits leishmania metabolism, a Phase III study in India demonstrated it as highly effective (Sundar 2002). Another randomized study in Ethiopia showed that among HIV-infected patients with leishmaniasis, miltefosine was less effective than sodium stibogluconate, but tolerability was better (Ritmeijer 2006). The doses was 100 mg daily (costs per month close to 2.300 Euro!). We have successfully treated some patients with miltefosine to date. Another option may be paromomycin, an aminoglycoside which seems to be effective as at least two randomized study from India showed (Sundar 2007+2011). In Europe paramomycin (Humatin®) has sofar only been licensed as a gastrointestinal drug for local use.

As a secondary prophylaxis pentamidine may be effective (Patel 2009). In contrast, fluconazole seems to show no effects (Rybniker 2009). Relapses are frequent and occur in almost half of all cases. ART seems to change this – another argument for inclusion in the AIDS classification (de La Rosa 2002, Fernandez-Cotarelo 2003).

References

Albrecht H, Sobottka I, Emminger C, et al. Visceral leishmaniasis emerging as an important opportunistic infection in HIV-infected persons living in areas nonendemic for Leishmania donovani. Arch Pathol Lab Med 1996, 120:189-98.

Albrecht H. Leishmaniosis – new perspectives on an underappreciated opportunistic infection. AIDS 1998, 12:2225-6.

de La Rosa R, Pineda JA, Delgado J, et al. Incidence of and risk factors for symptomatic visceral leishmaniasis among HIV type 1-infected patients from Spain in the era of HAART. J Clin Microbiol 2002, 40:762-7.

Fernandez-Cotarelo MJ, Abellan Martinez J, Guerra Vales JM, et al. Effect of highly active antiretroviral therapy on the incidence and clinical manifestations of visceral leishmaniasis in human immunodeficiency virus-infected patients. Clin Infect Dis 2003, 37: 973-7.

Lachaud L, Bourgeois N, Plourde M, et al. Parasite susceptibility to amphotericin B in failures of treatment for visceral leishmaniasis in patients coinfected with HIV type 1 and Leishmania infantum. Clin Infect Dis 2009, 48:e16-22.

Laguna F, Lopez-Velez R, Pulido F, et al. Treatment of visceral leishmaniasis in HIV-infected patients: a randomized trial comparing meglumine antimoniate with amphotericin B. AIDS 1999, 13:1063-9.

Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, Sundar S. Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980-2004. Lancet Infect Dis 2005, 5:763-74.

Patel TA, Lockwood DN. Pentamidine as secondary prophylaxis for visceral leishmaniasis in the immunocompromised host: report of four cases. Trop Med Int Health 2009, 14:1064-70.

Pintado V, Martin-Rabadan P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in HIV-infected and non-HIV-infected patients. A comparative study. Medicine (Baltimore) 2001, 80:54-73.

Ritmeijer K, Dejenie A, Assefa Y, et al. A comparison of miltefosine and sodium stibogluconate for treatment of visceral leishmaniasis in an Ethiopian population with high prevalence of HIV infection. Clin Infect Dis 2006, 43:357-64.

Rybniker J, Goede V, Mertens J, et al.  Treatment of visceral leishmaniasis with intravenous pentamidine and oral fluconazole in an HIV-positive patient with chronic renal failure – a case report and brief review of the literature. Int J Infect Dis. 2009 Aug 31.

Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 2002, 347:1739-46.

Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK. Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med 2007;356:2571-81.

Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. Lancet 2011, 377:477-86.

van Griensven J, Balasegaram M, Meheus F, et al. Combination therapy for visceral leishmaniasis. Lancet Infect Dis 2010, 10:184-194.

Microsporidiosis

Microsporidiosis is an important cause of diarrhea in HIV patients. Microsporidia are obligate intracellular protozoa. At least four genera, with Enterocytozoon bieneusi  considered the most noteworthy, are are described as pathogenic in humans.

Even in Germany, microsporidia were previously among the most recurrent diarrhea-causing microbes. Furthermore, in the pre-HAART era,  microsporidia could be found in approximately one-third of all patients.  Some studies documented up to two-thirds of all HIV-infected patients with chronic diarrhea (Sobottka 1998). The incidence of microsporidiosis has been reduced significantly due to ART; consequently, it is now only diagnosed occasionally. Although microsporidiosis is not AIDS-defining, chronic microsporidiosis almost always occurs in severely immunocompromised patients with CD4 T cell counts of less than 50 cells/µl.

Diarrhea may be very severe; watery, though not bloody; and accompanied by abdominal pain, nausea and vomiting. Fever is almost always absent. While myositis, keratoconjunctivitis and sinusitis have rarely been described, infections of the biliary ducts are considered as common.

In light of the fact that microsporidia, like cryptosporidia, are very small, an experienced laboratory is desirable for detection. Those who have never seen them or who are not asked to explicitly test for them will probably not detect them. Culture has not generally been established. Direct detection is most successful with specialized staining methods. Special transport or preparation is not necessary.

Although effective, albendazole (1-2 tbl. at 400 mg bid for 4 weeks) is not most advantageous in every case. For example, Enterocytozoon bieneusi is often resistant to albendazole. Repeated positive reports in such cases, especially from France, give an account of treatment with fumagillin (watch for thrombocytopenia), but these case numbers remain low (Molina 2002). Case reports (Bicart-See 2000) are also available for niazoxanide (see cryptosporidiosis). There have also been positive reports of symptomatic treatment with thalidomide. ART-induced immune reconstitution, however, seems to have the greatest effect (Carr 1998+2002, Maggi 2000).

References

Bicart-See A, Massip P, Linas MD, Datry A. Successful treatment with nitazoxanide of Enterocytozoon bieneusi microsporidiosis in a patient with AIDS. Antimicrob Agents Chemother 2000, 44:167-8.

Carr A, Cooper DA. Fumagillin for intestinal microsporidiosis. N Engl J Med 2002, 347:1381.

Carr A, Marriott D, Field A, Vasak E, Cooper DA. Treatment of HIV-1 associated microsporidiosis and cryptosporidiosis with combination antiretroviral therapy. Lancet 1998, 351:256-61.

Leder K, Ryan N, Spelman D, Crowe SM. Microsporidial disease in HIV-infected patients: a report of 42 patients and review of the literature. Scand J Infect Dis 1998, 30:331-8.

Maggi P, Larocca AM, Quarto M, et al. Effect of antiretroviral therapy on cryptosporidiosis and microsporidiosis in patients infected with HIV virus type 1. Eur J Clin Microbiol Infect Dis 2000, 19:213-7.

Molina JM, Tourneur M, Sarfati C, et al. Fumagillin treatment of intestinal microsporidiosis. N Engl J Med 2002, 346:1963-9.

Sobottka I, Schwartz DA, Schottelius J, et al. Prevalence and clinical significance of intestinal microsporidiosis in HIV-infected patients with and without diarrhea in Germany: a prospective coprodiagnostic study. Clin Infect Dis 1998, 26:475-80.

Nocardia

Nocardia are aerobic bacteria or actinomycetes that occur worldwide. Several species exist that cause pneumonia as well as systemic disease. In a survey of 30 cases of HIV patients with nocardiosis, pulmonary manifestation occurred in 21 cases (Uttamchandani 1994). Pulmonary manifestation of nocardiosis is often confused with tuberculosis. Extrapulmonary manifestation may occur in the skin, brain, nerves, muscle and bone. The immune response to Nocardia is cellular. As a result, there is generally an increased risk of pulmonary or systemic disease in immunosuppressed patients. In HIV infected patients, however, opportunistic infections with Nocardia are rare. Patients are usually significantly immunocompromised (Javaly 1992, Uttamchandani 1994). Nocardia respond well to sulfonamides such as sulfadiazine even in HIV infected patients (Pintado 2003). In cases of suspected nocardiosis, an experienced laboratory should be consulted.

References

Javaly K, Horowitz HW, Wormser GP. Nocardiosis in patients with HIV infection. Report of 2 cases and review of the literature. Medicine 1992,71:128-38.

Pintado V, Gomez-Mampaso E, Cobo J, et al. Nocardial infection in patients infected with the HIV. Clin Microbiol Infect 2003, 9:716-20.

Uttamchandani RB, Daikos GL, Reyes RR, et al. Nocardiosis in 30 patients with advanced HIV infection: clinical features and outcome. Clin Infect Dis 1994, 18:348-53.

Penicillium marneffei

Most fungi belonging to the Penicillium species are not pathogenic. One exception is Penicillium marneffei, which is a problem mainly for HIV patients in Southeast Asia (Le 2011). In these areas, it is the most frequent fungal infection in AIDS beside cryptococcosis, and is considered AIDS-defining by many clinicians (but is not included in the CDC classification). The known reservoirs for Penicillium marneffei are humans, rats and dogs.

Lungs and skin are the organs most frequently affected (Ma 2005). The clinical symptoms consist of prolonged high fever, lymphadenopathy, weight loss, malaise, cough and hemoptysis, diverse cutaneous and mucocutaneous lesions (reminiscent of molluscum contagiosum) and abnormal liver enzymes. There is often hepatosplenomegaly. Disseminated cases also occur (Ma 2005).

Definitive diagnosis relies upon the identification or isolation of P. marneffei in clinical specimens (blood, bone marrow, sputum). However, conventional culture usually takes at least three days. The use of the Galaktomannan antigen assay may facilitate earlier diagnosis of Penicillium marneffei infection for HIV-infected patients in areas of endemicity (Huang 2007).

There are no randomized studies which have evaluated different treatment options for P. marneffei infections. Amphotericin B, voriconazole and itraconazole are effective treatments (Supparatpinyo 2007, Ustianowski 2008). To prevent relapses, however, patients who have had the disease should take itraconazole as a permanent prophylaxis (Supparatpinyo 1998). Primary prophylaxis is not recommended even with longer stays in endemic areas (Chariyalertsak 2002). The only patient we have seen with Penicillium marneffei had spent several months on vacation in Thailand (Sobottka 1996).

References

Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis 2002, 34:277-84.

Huang YT, Hung CC, Liao CH, et al. Detection of circulating galactomannan in serum samples for diagnosis of Penicillium marneffei infection and cryptococcosis among patients infected with HIV. J Clin Microbiol 2007;45:2858-62.

Le T, Wolbers M, Chi NH, et al. Epidemiology, Seasonality, and Predictors of Outcome of AIDS-Associated Penicillium marneffei Infection in Ho Chi Minh City, Viet Nam. Clin Infect Dis 2011, 52:945-52.

Ma ES, Ho PL. Disseminated Penicillium marneffei infection. Br J Haematol 2005, 130:2.

Sobottka I, Albrecht H, Mack D, et al. Systemic Penicillium marneffei infection in a German AIDS patient. Eur J Clin Mic Inf Dis 1996,15:256-9.

Supparatpinyo K, Perriens J, Nelson KE, Sirisanthana T. A controlled trial of itraconazole to prevent relapse of Penicillium marneffei infection in patients infected with the HIV. N Engl J Med 1998, 339:1739-43.

Supparatpinyo K, Schlamm HT. Voriconazole as therapy for systemic Penicillium marneffei infections in AIDS patients. Am J Trop Med Hyg 2007;77:350-3.

Ustianowski AP, Sieu TP, Day JN. Penicillium marneffei infection in HIV. Curr Opin Infect Dis 2008;21:31-6.

Rhodococcus

Rhodococcus equi (previously Corynebacterium equi) is a sporeless, gram-positive intracellular pathogen, which is ubiquitous in air, water and soil. R. equi has been found on all continents, and was first identified as a pathogen in young horses. For half a century, only veterinarians were interested in this microorganism, but in the last two decades, it has been found more and more frequently in humans, primarily in significantly immunocompromised patients. In these patients, it causes severe granulomatous or abscess forming pneumonia, and sometimes also disseminated infection. The coryneform bacteria seen in sputum cultures are often confused with normal diphtheroid flora found in the mouth and therefore not diagnosed.

In 1986, the first case with respect to an AIDS patient was described (Samies 1986). In a collection of 78 cases, mostly AIDS patients with less than 50 CD4 T cells/µl were affected. The main symptoms were fever, dyspnea and unproductive cough (Capdevila 1997). Cavitation, mainly in the upper lobes, is frequently seen radiologically (Capdevila 1997, Marchiori 2005). Rhodococci are best detected in sputum and blood cultures (Torres-Tortosa 2003).

Erythromycin, azithromycin, ciprofloxacin, rifampin and vancomycin are effective, and some of these drugs can also be combined. However, treatment is difficult and complete recovery is rare, even with ART (Plum 1997, Sanz-Moreno 2002). Surgical measures may also be necessary if there is extensive cavitation.

Survival of patients treated with ART is much higher than that of patients who did not receive ART (Torres-Tortosa 2003, Topino 2010).

References

Capdevila JA, Bujan S, Gavalda J, Ferrer A, Pahissa A. Rhodococcus equi pneumonia in patients infected with the HIV. Report of 2 cases and review of the literature. Scand J Infect Dis 1997, 9:535-41.

Marchiori E, Muller NL, de Mendonca RG, et al. Rhodococcus equi pneumonia in AIDS: high-resolution CT findings in five patients. Br J Radiol 2005, 78:783-6.

Plum G, Fätkenheuer G, Hartmann P, et al. Secondary prophylaxis of Rhodococcus equi pneumonia in HIV infection: breakthrough despite rifampicin/erythromycin suppressive therapy. Clin Microbiol Infect 1997, 3:141-143.

Samies JH, Hathaway BN, Echols RM, et al. Lung abscess due to Corynebacterium equi: report of the first case in a patient with AIDS. Am J Med 1986, 80:685–688.

Sanz-Moreno J, Flores-Segovia J, Olmedilla-Arregui G, et al. Rhodococcus equi pneumonia: HAART helps but does not cure lung infection. AIDS 2002, 16:509-11.

Topino S, Galati V, Grilli E, Petrosillo N. Rhodococcus equi infection in HIV-infected individuals: case reports and review of the literature. AIDS Patient Care STDS 2010, 24:211-22.

Torres-Tortosa M, Arrizabalaga J, Villanueva JL, et al. Prognosis and clinical evaluation of infection caused by Rhodococcus equi in HIV-infected patients: a multicenter study of 67 cases. Chest 2003, 123:1970-6.

Trypanosoma cruzi

Trypanosoma cruzi is a protozoan that is transmitted via contaminated feces of tri-atomid bugs (assassin bugs), found almost exclusively on the American continent. It causes Chagas disease, one of the most frequent causes of cardiomyopathy in South America.

HIV-infected patients are more frequently affected and have higher levels of parasitemia (Sartori 2002), probably due to the fact that the Trypanosoma-specific immune response is mainly cellular in nature. In addition, a more frequent occurrence in HIV infected patients is meningoencephalitis, which is usually severe and radiologically not distinguishable from cerebral toxoplasmosis or primary cerebral lymphoma. Most probably it is a reactivation (Diazgranados 2009). In HIV-infected patients from South America, Trypanosoma infection should therefore be considered in the differential diagnosis (Silva 1999, Cordova 2008). Whenever possible, lumbar puncture should be performed because of the high accuracy for early diagnosis. However, treatment (for example benznidazole) is rarely successful and mortality is high (Sartori 2007, Cordova 2008). Possibly itraconazole or ketoconazole are also effective (de Almeida 2009).

References

Cordova E, Boschi A, Ambrosioni J, Cudos C, Corti M. Reactivation of Chagas disease with central nervous system involvement in HIV-infected patients in Argentina, 1992-2007. Int J Infect Dis 2008

de Almeida EA, Silva EL, Guariento ME, et al. Aetiological treatment with itraconazole or ketoconazole in individuals with Trypanosoma cruzi/HIV co-infection. Ann Trop Med Parasitol 2009, 103:471-6.

Diazgranados CA, Saavedra-Trujillo CH, Mantilla M, et al. Chagasic encephalitis in HIV patients: common presentation of an evolving epidemiological and clinical association. Lancet Infect Dis 2009, 9:324-30.

Silva N, O’Bryan L, Medeiros E, et al. Trypanosoma cruzi meningoencephalitis in HIV-infected patients. J AIDS Hum Retrovirol 1999, 20:342-9.

Sartori AM, Neto JE, Nunes EV, et al. Trypanosoma cruzi parasitemia in chronic Chagas disease: comparison between HIV-positive and HIV-negative patients. J Infect Dis 2002, 186:872-5.

Sartori AM, Ibrahim KY, Nunes Westphalen EV, et al. Manifestations of Chagas disease (American trypanosomiasis) in patients with HIV/AIDS. Ann Trop Med Parasitol 2007;101:31-50.

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Filed under 11. Opportunistic Infections, Part 3 - AIDS, Rare OIs