International Journal of Infectious Diseases
Volume 13, Issue 6 , Pages e467-e469, November 2009

Severe and long lasting cholestasis after high-dose co-trimoxazole treatment for Pneumocystis pneumonia in HIV-infected patients—a report of two cases

Department of Internal Medicine I, University Hospital, University of Regensburg, 93042 Regensburg, Germany

Received 20 July 2008; received in revised form 25 November 2008; accepted 15 December 2008. published online 19 March 2009.

Corresponding Editor: Meinolf Karthaus, Munich, Germany

Article Outline

Summary 

Pneumocystis pneumonia (PCP), a common opportunistic infection in HIV-infected individuals, is generally treated with high doses of co-trimoxazole. However, treatment is often limited by adverse effects. Here, we report two cases of severely immunocompromised HIV-infected patients who developed severe intrahepatic cholestasis, and in one patient lesions mimicking liver abscess formation on radiologic exams, during co-trimoxazole treatment for PCP. Whereas patient 1 showed lesions of up to 1cm readily detectable on magnetic resonance imaging under prolonged co-trimoxazole treatment, therapy of patient 2 was switched early.

Keywords: HIV, Pneumocystis pneumonia, Trimethoprim–sulfamethoxazole, Adverse effects, Intrahepatic cholestasis

 

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Introduction 

The incidence of opportunistic infections in HIV-positive patients has dramatically decreased since the arrival of highly active antiretroviral therapy (HAART) regimens. However, Pneumocystis pneumonia (PCP) remains one of the most frequent opportunistic infections and a leading cause of death in severely immunocompromised HIV-infected patients.1, 2 The preferred drug therapy for severe PCP is co-trimoxazole (trimethoprim–sulfamethoxazole). Due to the high doses necessary in PCP, treatment is often limited by severe side effects such as hepatotoxicity, rash, anemia, thrombocytopenia, and neutropenia. Here, we report the cases of two young HIV-infected patients who developed liver toxicity and lesions mimicking liver abscesses during co-trimoxazole treatment for PCP.

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Case 1 

A 24-year-old Asian male was admitted to our hospital with atypical pneumonia, rapid respiratory deterioration, and progressive pulmonary infiltrates. A diagnosis of advanced HIV-infection with a CD4 cell count of 15/μl and a viral load of 46 000 copies/ml was made. Bronchoalveolar lavage revealed Pneumocystis jirovecii and treatment was initiated with trimethoprim–sulfamethoxazole (co-trimoxazole; 20mg trimethoprim per kg) IV and 50mg prednisolone. The patient developed respiratory failure after 10 days requiring mechanical ventilation for 14 days. Antiretroviral therapy with nelfinavir, stavudine, and lamivudine was initiated after clinical recovery and extubation.

However, laboratory values showed rising alanine aminotransferase (ALT) with a maximum of 180 U/l (normal <22) combined with an elevated alkaline phosphatase (ALP) of 1414 U/l (normal <170) and a bilirubin of 1.3mg/dl (normal <1.0). No obstructive cholestasis could be detected by sonography. Further investigation showed cytomegalovirus (CMV) viremia (with a viral load of 100–1000 CMV copies/ml in peripheral blood), and additional therapy with ganciclovir IV was initiated. PCP therapy was switched to prophylactic dosing, accompanied by further improvement of the patient's condition. However, cholestasis parameters remained elevated. The further clinical course was complicated by Candida esophagitis and generalized seizure (without abnormalities in computed tomography (CT) or liquor).

Eight weeks after initial admission, while on co-trimoxazole prophylaxis for PCP, the patient developed jaundice and fever up to 40°C (leukocyte count 14.3×109/l , ALT 63 U/l, ALP 964 U/l, bilirubin 3.3mg/dl). Both sonography and magnetic resonance (MR) tomography showed lesions mimicking liver abscess formation with diameters of up to 1.3cm (Figure 1). Two subsequent biopsies of the intrahepatic lesions did not reveal liver abscesses and did not show any pathogens. Histology revealed cholestasis and cholangitis with mild hepatitis compatible with toxic liver damage. The size of the lesions and ALP values slowly decreased after adding ursodeoxycholic acid and without any further change in therapy. Co-trimoxazole prophylaxis was stopped after 11 months with rising CD4 counts of >300/μl.

During the following clinical visits, the patient continued to have elevated ALT and ALP values without jaundice or other changes in his general condition, whereas MR tomography showed a significant reduction of liver lesions (both in size and number). After a follow-up of 4 years, laboratory values have declined further with an ALT of 185U/l and an ALP of 319U/l.

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Case 2 

A 24-year-old Caucasian male was admitted to our intensive care unit (ICU) with PCP and further respiratory deterioration under mechanical ventilation. Co-trimoxazole treatment (20mg trimethoprim per kg IV) had already been initiated. Subsequent tests revealed advanced HIV-infection with an initial CD4 count of 2/μl and a viral load of 91 000 copies/ml. After a complicated clinical course with bilateral pneumothorax he gradually recovered, and antiretroviral therapy with zidovudine, lamivudine, and boostered lopinavir was started after significant improvement of his respiratory situation. Similar to case 1, severe Candida esophagitis and generalized seizures without any detectable abnormalities in CT occurred as further complications.

After 14 days at the ICU, he developed jaundice and liver value abnormalities, with an ALT of up to 381 U/l and an elevated ALP of 4351 U/l without obstructive cholestasis being detectable by ultrasound examination. Endoscopic cholangiography was suggestive of secondary sclerosing cholangitis. Having a viral load of 10 000 CMV copies/ml in peripheral blood, therapy with ganciclovir was added. Liver biopsy showed infiltration by granulocytes, mild cholangitis, cholestasis, and a centrilobular microabscess formation, whereas all microbiological diagnostics (including Grocott staining for fungi and PCR for Pneumocystis, Candida, and CMV) failed to detect any intrahepatic pathogens. Because of suspected drug-related liver toxicity, all drug treatments possibly implicated were terminated or changed. Co-trimoxazole was initially substituted with atovaquone and later changed to dapsone. ALP values reached a maximum of 8133 U/l with a bilirubin of 18.9mg/l.

Within the next 8 weeks, the patient was intermittently re-admitted to the ICU and eventually required mechanical ventilation due to recurrent pneumothoraces. After improvement in his general condition, he was sent to a rehabilitation institution with laboratory values of ALT 74 U/l, ALP 2261 U/l, and bilirubin of 13mg/l. The CD4 count was 15/μl and the viral load 100 copies/ml. However, 6 months after initial admission he was re-admitted to the hospital due to general clinical deterioration and died shortly thereafter of sepsis with multiple organ failure; an autopsy was declined by the relatives.

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Discussion 

PCP remains one of the most common opportunistic infections in HIV-infected patients. Severe PCP with respiratory failure eventually requiring mechanical ventilation is associated with a high mortality (exceeding 60% in some studies).3 The most effective treatment for severe PCP is co-trimoxazole. Alternatively, pentamidine may be used, but this is considered a second-line agent due to serious adverse effects.

However, the use of co-trimoxazole is often limited by toxicity. Most frequent are rash, drug fever, liver function abnormalities, anemia, neutropenia, and thrombocytopenia.4, 5 The rate of side effects experienced by HIV-infected patients appears to be considerably higher than in the general population (24–83% vs. ∼8%4, 6, 7, 8). Hepatotoxicity with elevated liver enzymes is a well-known side effect of co-trimoxazole. Other reports have associated the drug with cholestatic liver disease9, 10 and pancreatitis,11, 12, 13 and rarely a vanishing bile duct syndrome following the administration of co-trimoxazole9, 14 has been described. However, to the best of our knowledge, only one previous anecdotal report of focal hepatic lesions in combination with co-trimoxazole treatment has been published.15

The two patients presented here had severe PCP and were seriously immunocompromised (reflected by low CD4 count, Candida esophagitis, and CMV reactivation). Both developed liver enzyme alterations (elevated ALT with more pronounced elevations in ALP and bilirubin) within days after onset of high-dose IV co-trimoxazole therapy, initially without detectable liver abnormalities on sonography. Patient 2 (with a more fulminant course and higher liver enzymes) had a liver biopsy performed early in the course of disease, which yielded hepatitis, cholestasis, and cholangitis with microabscess formation and infiltration by granulocytes. Liver lesions suggesting abscess formation in severely immunocompromised patients may present a diagnostic challenge. The differential diagnosis includes secondary bacterial and other opportunistic infections, such as mycobacteria and invasive candidiasis; rarely even Pneumocystis jirovecii infection of the liver has been reported.16, 17 Thus, it appears crucial to exclude infectious complications before diagnosing a drug-related adverse event. Surprisingly, both patients had CMV infection diagnosed at the time of liver lesions. However, since PCR was negative, CMV infection as the main cause of liver lesion formation appears unlikely. Chronic disseminated candidiasis might present with similar clinical features and might be visible for years. However, both patients were already receiving fluconazole treatment for Candida esophagitis, and liver biopsies failed to detect fungi. We cannot rule out Pneumocystis itself as a causative agent, at least for patient 1. However, PCR for Pneumocystis was negative in a liver biopsy performed in patient 2. Furthermore, the contribution of other drugs administered during the ICU stay (e.g., sedatives) remains unclear.

For patient 2, all hepatotoxic drugs (including co-trimoxazole) were switched immediately, which was feasible due to the ameliorating pneumonia. Hereafter, cholestasis parameters declined. The fatal outcome most likely has to be attributed to immunosuppression (CD4 count still below 50/μl) and his compromised general condition with critical care illness and several recurrent pneumothoraces. In contrast, patient 1 continued to be on co-trimoxazole treatment despite elevated liver enzymes. Lesions suggesting abscess formation were discovered by MR tomography several weeks later, after an episode of fever, with diameters of more than 1cm (Figure 1). The long exposure to co-trimoxazole may well be responsible for the protracted and more severe course. The lesions were still detectable several years later on abdominal sonography.

In summary, lesions suggesting liver abscess formation may be due to cholestatic hepatotoxicity in patients treated with high doses of co-trimoxazole for severe PCP. Patients should be monitored carefully and a switch of therapy may be an option when rising liver enzymes and/or cholestasis parameters are observed.

Conflict of interest: No conflict of interest to declare.

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References 

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PII: S1201-9712(09)00068-X

doi:10.1016/j.ijid.2008.12.016

International Journal of Infectious Diseases
Volume 13, Issue 6 , Pages e467-e469, November 2009

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