Pneumocystis pneumonia (PCP) is one of the most critical and life-threatening infections in immunocompromised patients with AIDS (especially CD4+ T cell less than 0.2×109/L), hematological malignancies, organ transplantation or connective tissue diseases.1 It is caused by a fungus called Pneumocystis jiroveci (P. jiroveci, formerly called P. carinii).2 Despite treatment with trimethoprim-sulfamethoxazole (TMP/ SMZ) and corticosteroids, the morbidity of this disease is often high because of late treatment or contraindications of sulfanilamide. New therapeutic approaches are therefore warranted. Caspofungin, a beta-1, 3-glucan synthesis inhibitor, has shown activity against P. jiroveci in experimental animals,3 but clinical trials about this are rare.4-8 We here report our clinical experience with caspofungin in salvage treatment of severe PCP in a patient with chronic myelomonocytic leukemia (CMML) and uremia.
A 76-year-old man with chronic myelomonocytic leukemia was admitted to the hematological ward of this hospital because of melena for 8 months and dyspnea for 1 month. At admission 4 years ago he was diagnosed as having chronic myelomonocytic leukemia and treated by oral hydroxycarbamide 0.5 mg per day until now; 3 years ago he suffered from chronic renal dysfunction after chemotherapy. He had coronary heart disease for 8 years and no unhealthy hobbies. On physical examination, chest auscultation was normal. He had abdominal distention and hepatosplenomegaly but no other significant signs were found. Arterial blood gas analysis on admission showed pH 7.352, PaCO2 30.7 mm Hg, and PaO2 78 mm Hg at room temperature. Other pertinent laboratory findings included a leukocyte count of 18.60×109/L with a differentiation of 47% polymorphonuclear cells, 13% lymphocytes, and 30% immature cell, hemoglobin of 7.5 g/L, platelets of 96×109/L and serum creatinine of 170 μmol/L. Chest X-ray was normal (Figure 1).
After admission he continued to be treated by hydroxycarbamide 0.5 mg per day and received no other therapies. Three days after admission he got a fever of 39°C and increasingly aggravated dyspnea, and chest auscultation demonstrated few bibasilar rales. Laboratory examinations showed that leukocyte count was 25.5×109/L with 32% immature cells and CD4+ T cell 0.969×109/L, C-reactive protein (CRP) was 98.18 mg/L, lactate dehydrogenase (LDH) was 872 IU/L, and HIV antibodies were negative in serum. He was given supplemental oxygen and intravenous clindamycin plus imipenem/cilastatin for 7 days. However his condition deteriorated and arterial blood gas analysis on May 13 (10 days after admission) showed pH 7.352, PaCO2 22.9 mm Hg, and PaO2 49 mm Hg on 50% oxygen without rebreathing mask. Sputum, blood, and urine cultures were sterile; smears for acid-fast bacilli and tests for viral antibodies were both negative. The leukocyte count increased to 51.8×109/L, and the dosage of hydroxycarbamide increased to 1.5 mg per day. One day later the leukocyte count decreased to 15.2×109/L, but he developed hyperuricemia, hyperphosphatemia,
hyperkalemia, and oliguria; his renal function worsened and the condition was diagnosed as oncolysis syndrome. Chest X-ray showed diffuse infiltration in both lung fields (Figure 2) and chest high resolution computed tomography (HRCT) revealed bilateral diffuse ground glass opacities and consolidations in the lung fields (Figure 3).
Twelve days after admission (May 15, 2008), the patient was transferred to respiratory intensive care unit (RICU) and placed on a noninvasive positive pressure ventilator (NIPPV). Gradually the patient became unconscious; subsequently he was placed on an invasive mechanical ventilator (IPPV) and underwent continuous renal replacement therapy (CRRT). The plasma level of (1, 3)-beta-D-glucan (G test) was 30 pg/ml (normal range <10 pg/ml) and galactomannan assay in serum (GM test) was negative before CRRT. Because the patient's diagnosis remained elusive and pulmonary infections caused by some pathogens such as fungi or P. jiroveci could not be excluded, caspofungin was added to his therapy with a loading dosage of 70 mg on the first day in RICU and a maintenance dose of 50 mg daily. TMP/ SMZ could not be added because of uremia. Meanwhile, methylprednisolone 80 mg/d was administrated for severe respiratory failure. One day after caspofungin therapy, the patient regained consciousness; 3 days after caspofungin therapy, his body temperature became normal and Chest X-ray improved greatly (Figure 4).
Gomori methenamine silver staining (GMS) of sputum and bronchoalveolar lavage fluid (BALF) both revealed P. jiroveci cysts (Figure 5) and the P. jiroveci-RNA was also positive in BALF and sputum detected by PCR 3 days after caspofungin therapy. Then TMP/SMZ (1 g daily) was added intravenously while the dosage was adjusted by renal function. Five days after caspofungin therapy, the patient succeeded in weaning to extubation; 8 days later, chest HRCT improved greatly (Figure 6); 14 days later. GMS and PCR of sputum became negative and LDH of plasma became normal. (1, 3)-beta-D-glucan in plasma decreased to 5 pg/ml and PaO2 in arterial blood increased to 80 mmHg at room temperature. The period of caspofungin treatment lasted for 21 days and the patient continued to take orally TMP/SMZ for prophylaxis.
The disease known as PCP is one of the leading causes of illness and death in persons with impaired immunity, especially with AIDS. Pneumocystis organisms were first reported in animals by Chagas and Carinii nearly 100 years ago.9 A few years later, the organism was named Pneumocystis carinii (P. carinii, Pc) and widely thought to be a protozoan until 1988, when DNA analysis demonstrated that P. carinii is an odd fungus, lacking in ergosterol and very difficult to grow in culture.10 The organism that causes human PCP is now named Pneumocystis jiroveci (P. jiroveci, Pj), in honor of the Czech parasitologist Otto Jirovec, who is credited with describing the microbe in humans. Acronym "PCP" is retained, and now refers to "pneumocystis pneumonia".2
Common symptoms of PCP include the subtle onset of progressive dyspnea, nonproductive cough, and low-grade fever. Physical examination typically reveals tachypnea, tachycardia, and normal findings on lung auscultation.11 Typical radiographic features of pneumocystis pneumonia are bilateral perihilar interstitial infiltrates that become increasingly homogeneous and diffuse as the disease progresses (Figure 2).12 When chest radiographic findings are normal, HRCT, which is more sensitive than chest radiography, may reveal extensive ground glass attenuation or cystic lesions (Figure 3).13 Although an elevated serum LDH level has been noted in patients with PCP, it is likely to be a reflection of the underlying lung inflammation and injury rather than a specific marker for the disease.14
PCP may be difficult to diagnose owing to nonspecific symptoms and signs. Because P. jiroveci cannot be cultured, the diagnosis requires microscopical examination in order to identify P. jiroveci from clinical specimens such as sputum, induced sputum or BALF. Bronchoscopic or surgical lung biopsy is rarely needed. Trophic forms can be detected with Wright-Giemsa staining and cysts forms can be stained with Gomori methenamine silver (GMS).15 Under a light microscope, the cyst appears as a spherical, cup-shaped, or crescent-shaped object measuring 4 to 8 μm in diameter, containing dark bodies or dots in GMS staining (Figure 5). The routine cytological staining techniques have a high specificity (100%) but a lower sensitivity (<60%).16
The specialized technique such as polymerase chain reaction (PCR) has been shown to have greater sensitivity (100%) and specificity (87%) for the diagnosis of PCP than conventional staining when PCR primers for the gene for P. jiroveci mitochondrial ribosomal RNA (rRNA) are used.16 In patients with positive PCR results in BALF or sputum but with negative smears, clinical management of the disease remains a challenge. However, we recommend treatment of these patients if immunosuppression is ongoing.11
Whether cysts or trophics of P. jiroveci all possess glucan-rich walls, 1, 3-beta-D-glucan (G-test) in serum or BALF is a sensitive marker for the diagnosis of PCP.17 Its sensitivity is about 86.7%, especially higher in severe patients.18 Since BAL procedure is invasive, measuring 1, 3-beta-D-glucan should be considered as a primary modality for the diagnosis of PCP, especially for patients with severe respiratory failure.17 Furthermore, this marker is very useful for monitoring the treatment of PCP.19
TMP/SMZ is considered the first line therapy for PCP in adults and adolescents. The recommended dose is 15 mg/kg per day of TMP, in three to four divided doses for 21 days. Intravenous therapy and corticosteroids are preferred in patients with moderate to severe disease (defined by an A-a oxygen gradient greater than 35 mm Hg or an arterial oxygen pressure of less than 70 mm Hg) or in those with intolerable gastrointestinal upset.20 Clindamycin plus primaquine, inhaled pentamidine, trimetrexate and atovaquone are second-line options, while intravenous pentamidine may be used in more severe cases.11
Caspofungin (Cancidas, first semi-synthetic echinocandins, Merck Co. Ltd, USA), inhibitor of fungal 1, 3-beta-D-glucan synthesis,21,22 is effective for the treatment of invasive candidiasis and aspergillosis23 starting with a loading dosage of 70 mg and a maintenance dose of 50 mg daily, because of 1, 3-beta-D-glucan is the main component of fungal cell wall (for example: Candida and Aspergillus). Mammals have no cell walls; therefore caspofungin has little side effect on human bodies. Recent studies indicate that P. jiroveci is a fungal species possessing a glucan-rich cyst wall.24 Theoretically, caspofungin has activity against P. jiroveci, which has been confirmed in animal models,3 but clinical experiences are rarely reported.
Until now in the National Knowledge Infrastructure (CNKI, China) and PubMed Central database, there are only six articles (total 9 cases) on prescription of caspofungin succeeding against P. jiroveci.4-8 These articles reported 6 cases treated with combined TMP/SMZ. This preliminary clinical experience suggests that the addition of caspofungin to TMP/SMZ, which is active against trophic forms, may provide a synergistic activity against P. jiroveci by fully inhibiting the organism life cycle.6,7
Clinical difficulties of PCP in China included difficulties in diagnosis and treatment. (1) Clinicians usually ignore P. jiroveci infection in immunocompromised patients without AIDS. Although there are many methods for diagnosing PCP as mentioned above, only a few hospitals in China have put the techniques of P. jiroveci staining and Pj-PCR into practice. (2) The drugs against P. jiroveci commonly cause intolerance or adverse effects that may hamper the efficacy of treatment; many drugs such as pentamidine, trimetrexate and atovaquone are not available in most hospitals in China. Furthermore, in many times it is too late to treat because of delayed diagnosis.
THE AUTHORS' PERSONAL OPINIONS
Our patient had hematological malignancy. Three days after admission he presented with fever, dyspnea, and severe hypoxemia, and underwent intubation and mechanical ventilation. Chest imaging showed rapidly progressing diffuse infiltration in both lungs and had no response to antibiotic therapy. The concentration of 1, 3-beta-D-glucan (G-test) in plasma was elevated.17 Although the CD4+ T cell count of this patient was normal, PCP should be considered. Later GMS staining and PCR of BALF both confirmed this diagnosis.
At the very beginning, the patient's diagnosis remained elusive. Although PCP was suspected, TMP/SMZ could not be used because of uremia. Since single clindamycin did not make any improvement25 and pentamidine was not available in our hospital, caspofungin might be the best choice for this situation. Three days after caspofungin therapy, clinical manifestations were improved obviously; and 5 days later, the patient succeeded in weaning. Caspofungin as an agent for salvage treatment of severe PCP was successful in our patient.
The treatment of PCP with caspofungin is both effective and safe, especially in patients with suspicious PCP and contraindications for sulfanilamide, but more clinical trials are needed to prove its efficiency. Combined treatment of TMP/SMZ with caspofungin for severe PCP may be more effective. Concentrations of 1, 3-beta-D-glucan (G-test) in plasma or BALF are helpful to diagnose PCP and monitor its treatment.
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