Treatment of Pneumocystis jirovecii pneumonia in non-human immunodeficiency virus-infected patients using a combination of trimethoprim-sulfamethoxazole and caspofungin

lNTRODUCTlON

Approximately 75% of patients infected with human immunodeficiency virus(HIV)positive present withpneumonia(PJP)during the early stages of the infection[1].Technological advancements in medicine have led to development of effective therapies that have significantly reduced the incidence of PJP in patients with acquired immunodeficiency syndrome(AIDS).For example,the CD4T lymphocyte counts have been shown to be accurate in identifying patients at high clinical risk of developing PJP[2].In addition,prophylaxis interventions have been designed for patients at risk of PJP[3]and sensitive immunofluorescence detection methods are now available for timely detection.The development of combined antiretroviral therapy drugs has significantly reduced incidence of PJP and improved prognosis of HIV-positive PJP(HIV + PJP)patients[4].Clinically,the number of non-HIV-infected PJP patients has been on the rise annually owing to the increased use of immunosuppressants and organ transplantations[5,6].The mortality levels of non-HIV-infected PJP patients ranges between 30% and 60%,whereas the mortality of HIV + PJP patients ranges between 10% and 20%[7].In comparison,management measures for non-HIV-infected PJP are not standardized as is the case for HIV + PJP patients.Moreover,the clinical attention for non-HIV-infected patients is poorer compared with that of HIV + PJP patients.

The aim of this retrospective study was to explore the characteristics of non-HIV-infected PJP treated with trimethoprim-sulfamethoxazole(TMP-SMX)and caspofungin.The findings of this study are expected to improve our understanding of the occurrence of PJP in non-HIV-infected patients,and thus prevent misdiagnosis and reduce mortality rate of non-HIV-infected PJP patients.

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MATERlALS AND METHODS

Study design

A retrospective case review of 22 non-HIV-infected PJP patients admitted to Dongyang Hospital Affiliated to Wenzhou Medical University,a tertiary hospital in Zhejiang,China was carried out between October 2019 and April 2021.Patient data including symptoms,laboratory results,dynamic and comprehensive computed tomography data,and clinical course of the disease were extracted from electronic medical records.Information on treatment,response to treatment,outcomes,and any followup data were also collected.The study protocol was approved by the Ethics Committee of the Dongyang Hospital Affiliated to Wenzhou Medical University,(No.2021-YX-127).All data were anonymized prior to analysis.

RESULTS

Patient characteristics

In total,four women and 18 men diagnosed as non-HIV-infected PJP were enrolled in the study.The median age of these patients was 61.18 ± 16.51(range 17-84)years(Table 1).All patients tested positive forDNA fragments as determined using metagenomic nextgeneration sequencing(mNGS).Systematic screening did not identify any other respiratory pathogens at the time of hospital admission.All patients presented with dry cough and dyspnea,whereas 13 patients had fever.The median time from onset of illness to admission was 5.68 ± 3.66(range 1-15)d.On physical examination,the patients presented with heterogeneous and nonspecific clinical signs.Among the comorbidities found were autoimmune disease(= 5),non-Hodgkin’s lymphoma(= 4),lung cancer(= 7;all underwent chest radiotherapy),organ transplantation(= 2),and membranous nephropathy(= 4).All patients developed respiratory failure and received oxygen therapy(oxygen therapy,administered nasally for 11 patients,mask oxygen therapy for 10 patients,and high flow nasal cannula therapy for 1 patient).No patient received invasive mechanical ventilation.

Technical investigations

Clinical examination carried out at admission showed that patients had a mean white blood cell count of 9.69 ± 6.22 × 10/L and with a proportion of neutrophils of 0.82 ± 0.14%.In addition,C-reactive protein level was 79.69 ± 64.21 mg/L,lactate dehydrogenase(LDH)level was 408.23 ± 117.87 U/L,and procalcitonin level was 0.23 ± 0.21 ng/mL.

Lung imaging revealed lesions in the upper lobe of lung in the early stage.With progression of the disease,the lesions spread to the lower lobe of the lung.The most common imaging manifestation was widespread ground glass opacity,which had a mosaic or diffuses distribution,mainly in the upper lobe of the lung(Figures 1 and 2).

Treatment

Analysis of medical records showed that most of the patients were treated with antibiotics such as cephalosporin prior to admission.However,their symptoms gradually deteriorated leading to development of progressive dyspnea.After hospital admission,patients underwent bronchofibroscopy and alveolar lavage fluid was collected for mNGS analysis.

The population of HIV-negative patients susceptible toincludes patients who have undergone transplantation,hemato-oncological patients,and those taking immunosuppressive drugs for autoimmune diseases.Approximately 20% of non-HIV-infected PJP patients are those with autoimmune diseases,mainly nodular polyarteritis,granuloma with polyarteritis,dermatomyositis/polymyositis,and rheumatoid arthritis with interstitial pneumonia[17,18].So far,several drugs such as,long-term use of medium and high-dose glucocorticoids,cyclophosphamide,rituximab,alemtuzumab(a monoclonal antibody used for treatment of chronic B-cell lymphoblastic leukemia and multiple sclerosis),and tumor necrosis factor α antagonists have been linked to the occurrence of PJP[19,20].

Outcomes

After initiation of therapy,the body temperature gradually returned to normal within 3 d,and their respiratory function improved.Further analysis revealed that the level of inflammatory indices in blood significantly decreased,and the lung lesions gradually disappeared following treatment.All patients had fully recovered before discharge.

DlSCUSSlON

The incidence of PJP is high among immunocompromised HIV-negative patients.This calls for development of novel diagnostic,treatment,and prevention strategies for non-HIV-infected PJP[9-11].Non-HIV-infected PJP patients have an acute onset,rapid disease progression,poor prognosis,and higher mortality rates compared with HIV-infected PJP patients[12-16].

mNGS analysis was carried out within 48-72 h from the time of sample collection to the time results were reported.After confirmation of PJP,treatment was changed to TMP-SMX(TMP,15-20 mg/kg/d;SMX,75-100 mg/kg/d),administered for at least 2 wk,as reported previously[8].Patients received TMP-SMX combined with caspofungin(through intravenous administration of 70 mg QD on the first day and 50 mg QD as the maintenance dose afterwards)for those with respiratory failure or renal insufficiency.In addition,moderate to severe non-HIV-infected PJP patients received glucocorticoid treatment(= 17)for 1 wk.

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The authors declare that they have no competing interests.

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Incidence of non-human immunodeficiency virus(HIV)-infectedpneumonia(PJP)patients has been increasing annually owing to increased use of immunosuppressants and organ transplantation.In addition,management of non-HIV-infected PJP patients is not standardized as it is the case for HIV-infected PJP patients,and the clinical attention is poor compared with that of HIVinfected PJP patients.

Current guidelines and published reviews state that the first-line treatment for non-HIV-infected PJP is TMP-SMX[7,8,28].However,prolonged use of TMP-SMX may increase risk of drug resistance and side effects.Some patients cannot tolerate high doses of this treatment however,low-dose therapy is well-tolerated and has fewer side effects[29].In the current study,one patient developed renal impairment during treatment,but renal function was restored when the dosage was reduced.Therefore,the dose of TMP-SMX should be adjusted based on the renal function of the patient.If the patient is taking immunosuppressants during treatment,the dose of immunosuppressants should be reduced,suspended,or stopped.However,the dose should be individualized.Previous studies have shown that caspofungin alone or in combination with TMP-SMX is effective for HIV-infected PJP patients,and caspofungin can also be used as a remedial drug[30,31].In the current study,all patients were successfully treated with caspofungin combined with TMP-SMX.This finding indicates that caspofungin can cure PJP;however,these findings should be validated in large-sample clinical studies.According to current guidelines,standard treatment should be used for 2-3 wk[8].The duration should be appropriately extended until respiratory function is stable for non-HIV-infected PJP patients with severe immunosuppression,high pneumocystis load,and slow clinical improvement[8,28].Non-HIVinfected PJP patients present with severe inflammation and some studies recommend use of adjuvant glucocorticoid to control it[31].In the current study,17 patients underwent adjuvant treatment of glucocorticoids for 7 d with good results.This indicates that patients with moderate to severe disease should be put under adjunctive corticosteroids to improve survival.

CONCLUSlON

Non-HIV-infected PJP patients manifest with rapid disease progression,respiratory failure,and high mortality.Physicians should be aware that PJP is an important infectious complication in hematooncological and post-transplant patients,including who undergo solid organ transplant,allogenic or autologous hematopoietic stem cell transplantation.It is also common in patients taking immunosuppressive drugs.For non-HIV-infected PJP patients with respiratory failure,or patients with renal insufficiency,TMP-SMX combined with caspofungin can alleviate symptoms and accelerate recovery.Several challenges are encountered in the treatment of non-HIV-infected PJP patients,such as difficulty of determining the timing and duration of adjunctive treatment using glucocorticoids and identification of patients susceptible toinfection.Therefore,future studies should explore methods to circumvent these challenges.

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ARTlCLE HlGHLlGHTS

Research background

cannot be cultured in the laboratory.Therefore,this infection has been traditionally diagnosed based on microscopic observation of the organisms in respiratory specimens.However,due to the lower pathogen burden in non-HIV-infected PJP patients compared with HIVinfected PJP patients,specimens from non-HIV-infected PJP patients have lower microscopic sensitivity[24,25].A combination of different diagnostic methods,such as microscopy,polymerase chain reaction,and(1,3)-β-D-glucan detection have been previously adopted to increase the diagnosis rate.Silver staining can detect cysts with high specificity.However,the sensitivity of this method is not satisfactory.PJP patients have a higher number of trophozoites than cysts,thus Giemsa and Diff-Quik stains used for the detection of trophozoites should have high sensitivity.Moreover,the results depend on the skill and experience of the examiner.Advances in technology have led to development of mNGS which can unbiasedly detect various pathogenic microorganisms in clinical samples.This approach ensures rapid screening of pathogens,and provides timely identification of pathogens.Therefore,it is currently applied in the detection of pathogens that cause infectious diseases.Bronchoalveolar lavage fluid(BALF)is the preferred specimen,as BALF provides a higher diagnosis rate,and can be used to identify other pathogens,such as tuberculosis,histoplasmosis and cytomegalovirus infection.Induced sputum testing can be used as an alternative method if the patient cannot tolerate bronchoscopy,however,its diagnostic sensitivity is lower compared to that of BALF(55%-90%)[26,27].

Research motivation

The aim of this retrospective study was to explore the characteristics of non-HIV-infected PJP treated with trimethoprim-sulfamethoxazole(TMP-SMX)and caspofungin.

Research objectives

The findings of the current study will improve understanding of PJP in non-HIV-infected patients,and reduce misdiagnosis rate and mortality rate of non-HIV-infected PJP patients.

Research methods

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Research results

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Research conclusions

Non-HIV-infected PJP patients are characterized by rapid disease progression,high risk of respiratory failure,and high mortality.The findings of the current study showed that a combination of TMP-SMX and caspofungin is an effective treatment option for severe non-HIV-infected PJP patients with respiratory failure.

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A total of 22 cases of non-HIV-infected PJP were included in the current study.Clinical manifestations of patients mainly included fever,dry cough,and progressive dyspnea.All patients presented with an acute onset and respiratory failure.The most common imaging manifestation was ground glass opacity around the hilar,mainly located in the upper lobe.All patients underwent diagnosis using nextgeneration sequencing,and were all treated with TMP-SMX and caspofungin.Seventeen patients received short-term adjuvant glucocorticoid therapy.All patients recovered and were discharged from hospital.

Research perspectives

The timing and duration of adjunctive treatment using glucocorticoids and identification of patients susceptible toinfection at an early stage to start effective prophylaxis drugs.

FOOTNOTES

All authors contributed to the study conception and design;Material preparation and data analysis were performed by Feng LF and Chen YX;The first draft of the manuscript was written by Wu HH;Fang SY re-evaluated and added content on the computed tomography imaging outcomes;All authors were involved in the review of various previous versions of the manuscript;All authors have read and approved the final manuscript.

The study protocol was approved by the Ethics Committee of the Dongyang Hospital Affiliated to Wenzhou Medical University(No.2021-YX-127).

The main symptoms of non-HIV-infected PJP patients include fever,dyspnea and dry cough.Moreover,hypoxia and respiratory failure are more common in non-HIV-infected PJP patients compared with HIV-infected PJP patients.However,frequency of LDH elevation is lower,the onset and disease progression are more rapid(often within a few days)in non-HIV-infected PJP than in HIV-infected PJP.For non-HIV-infected PJP patients,physical examination is nonspecific,and lung auscultation is usually normal,but often inconsistent for those with severe clinical manifestations[21].Computed tomography(CT)scans show ground-glass opacity(GGO),mainly presenting with a central distribution,is a common radiological pattern for PJP patients.These manifestations were observed in patients included in the current study(Figure 1).GGOs may present as a mosaic-like distribution or diffuse distribution,more commonly occurring in the upper lobes of the lungs[22].In the advanced stages of the disease,CT scans show lung consolidation.Paving stone-like manifestations are observed in 6%-18% of patients[23].Hollowness and pleural effusion are rare,and if they occur,they often indicate existence of other diseases[23].Approximately 3%-6% of non-HIV-infected PJP patients may present with lung cyst-like changes of different shapes,sizes,and wall thicknesses,implying that they are susceptible to spontaneous pneumothorax[23].GGOs in non-HIV-infected PJP patients spread faster compared than in HIV-infected PJP patients.

A retrospective case review of 22 non-HIV-infected PJP patients admitted to Dongyang Hospital Affiliated to Wenzhou Medical University was conducted between October 2019 and April 2021.Patient data on symptoms,laboratory results,dynamic and comprehensive computed tomography,and clinical course of the disease were extracted from electronic medical records.Additional data on treatment,response to treatment,outcomes,and any relevant follow-up data were also collected.

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All data generated or analyzed during this study are included in this published article.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See: https://creativecommons.org/Licenses/by-nc/4.0/

China

Huan-Huan Wu 0000-0001-8324-9570;Shuang-Yan Fang 0000-0001-8713-1342;Yan-Xiao Chen 0000-0002-0428-6507;Lan-Fang Feng 0000-0001-7626-9389.

Zhang H

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Kerr C

Zhang H