Category Archives: Rare OIs

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