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Pneumocystis pneumonia in HIV-1-infected patients
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Review
Pneumocystis pneumonia in HIV-1-infected patients Satoshi Shibataa, Toshiaki Kikuchib,n a
Department of Respiratory Medicine, Niigata City General Hospital, Niigata 950-1197, Japan Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori, Chuoku, Niigata 951-8510, Japan
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art i cle i nfo
ab st rac t
Article history:
Pneumocystis pneumonia (PCP) is an opportunistic disease that mainly affects patients with
Received 30 October 2018
a deficiency of cell-mediated immunity, especially acquired immunodeficiency syndrome
Received in revised form
(AIDS). The incidence of PCP in these patients has declined substantially owing to the
12 January 2019
widespread use of antiretroviral therapy and PCP prophylaxis. However, PCP is still a major
Accepted 30 January 2019
AIDS-related opportunistic infection, particularly in patients with advanced immunosuppression in whom human immunodeficiency virus type 1 (HIV-1) infection remains undiagnosed or untreated. The clinical manifestations, diagnosis, treatment, and
Keywords:
prevention of PCP in patients with HIV-1 infection are addressed in this review.
Pneumocystis pneumonia Acquired immunodeficiency
& 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
syndrome Human immunodeficiency virus Opportunistic infection
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Biology and epidemiology . . . . . . . . . . . . . . . Transmission . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations . . . . . . . . . . . . . . . . . Radiological findings . . . . . . . . . . . . . . . . . . . Serum markers used in the diagnosis of PCP Definitive diagnosis . . . . . . . . . . . . . . . . . . . . Disease prevention . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abbreviations: A-aDO2, BAL, HRCT, PaO2,
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alveolar-arterial O2 gradient; AIDS,
bronchoalveolar lavage; BDG, (1–3)-β-d-glucan; GGO, high-resolution computed tomography; IRIS, partial pressure of atrial oxygen; PCP,
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acquired immunodeficiency syndrome; ART,
ground-glass opacity; HIV,
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antiretroviral therapy;
human immunodeficiency virus;
immune reconstitution inflammatory syndrome; LDH,
Pneumocystis pneumonia; PCR,
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lactate dehydrogenase;
polymerase chain reaction; SMX,
sulfamethoxazole;
TMP, trimethoprim n Corresponding author. Fax: þ81 25 368 9326. E-mail address: [email protected] (T. Kikuchi). https://doi.org/10.1016/j.resinv.2019.01.009 2212-5345/& 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
8.1. Adjunctive corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Timing of ART initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. IRIS associated with PCP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
Biology and epidemiology
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source was postulated. Firas et al. provided quantitative data on the spread of P. jirovecii in the exhaled air from infected patients [14]. The resulting organism burden in air samples decreased with increasing distance from the patient. These data suggested airborne, person-to-person transmission of P. jirovecii from infected patients to immunocompromised hosts. Thus, patients with PCP should not be allowed in the same room as other immunocompromised patients, but data are insufficient to recommend this as a standard practice.
Pneumocystis was identified in 1909 and 1910 by Carlos Chagas and Antonio Carini. Initially, the organism was assumed to be part of the life cycle of Trypanosoma cruzi. However, in 1912, Pneumocystis was recognized as a new genus by Delanoe, who named it Pneumocystis carinii in honor of the work of Antonio Carini [1,2]. Pneumocystis was long thought to be a genus of protozoa, but ribosomal RNA sequencing later revealed it to be a fungus [3]. The nomenclature of Pneumocystis was also changed, from Pneumocystis carinii, which infects rats, to Pneumocystis jirovecii, which infects humans [4]. Despite the passage of more than 100 years since Pneumocystis was first identified, Pneumocystis pneumonia (PCP) was largely unrecognized until the 1980s. In 1981, several young, previously healthy, men who have sex with men were diagnosed with multiple episodes of PCP [5]. This was the first clinical evidence of a disease that would later become known as acquired immunodeficiency syndrome, or AIDS. Its causative agent, the human immunodeficiency virus type 1 (HIV-1), was identified in 1983. Following the onset of the AIDS epidemic, in 1982, there was a marked increase in the incidence of reported cases of PCP. In the late 1980s, an estimated 75% of HIV-1-infected patients had developed PCP [6]. With the introduction of antiretroviral therapy (ART) and chemoprophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), the incidence of PCP in HIV-1-infected patients has decreased substantially. However, it is still a serious health concern in people living with HIV/AIDS and one of the leading causes of opportunistic infection in this population.
HIV-1-infected patients with PCP (HIV-PCP) typically present with a nonproductive cough, fever, dyspnea, chest discomfort, and malaise that progress over days to weeks. However, up to 7% of these patients can be asymptomatic [15]. By contrast, PCP in non-HIV-1-infected patients (non-HIV-PCP), such as those undergoing anti-malignancy chemotherapy or being treated with immunosuppressive agents, is more likely to be of acute onset and will often cause severe respiratory distress within the first several days. Disease characteristics of HIV-PCP and non-HIV-PCP are summarized in Table 1. Lung auscultation is usually normal, but inspiratory crackles may be detected in some patients. Hypoxemia ranges from mild at room air [partial pressure of atrial oxygen (PaO2) Z70 mm Hg or alveolar-arterial O2 gradient (A-aDO2) o35 mm Hg] to moderate (A-aDO2 Z35 and o45 mm Hg) to severe (A-aDO2 Z45 mm Hg). The approach to treatment is based on the severity of disease and is described below.
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4.
Transmission
The route of Pneumocystis transmission is not well understood. Serologic studies have shown that, by 4 years of age, two-thirds of normal children have antibodies to P. jirovecii [7]. In a nested polymerase chain reaction (PCR) study, Ponce et al. identified P. jirovecii in 64.9% of the autopsied lungs of healthy adults [8]. These findings suggested unapparent infection in the normal population, and in immunocompromised patients, PCP was thought to represent the reactivation of a latent infection. However, an animal study showed the clearance of Pneumocystis after infection, and several possible routes of subsequent transmission were reported [9–12]. Laurence et al. reported that 54% of patients with PCP who were newly diagnosed with HIV-1 and never exposed to sulfa drugs had a mutation in the dihydropteroate synthase (DHPS) gene, which confers resistance to sulfa drugs [13]. Because this mutation is associated with prior exposure to a sulfa drug, recent acquisition of the fungus from an exogenous
3.
Clinical manifestations
Radiological findings
On chest radiography, the most common abnormalities of PCP in both HIV-1-infected and non-HIV-1-infected patients are diffuse bilateral ground-glass opacities (GGOs) or an alveolar pattern. However, normal findings on a chest Table 1 – Characteristics of PCP in HIV-infected and nonHIV-infected patients. HIV-PCP
Non-HIV-PCP
Main symptoms
Fever, shortness of breath, nonproductive cough Severity of symptoms Moderate Severe Onset Subacute Acute Disease course Slow Rapid Progression In weeks In days PCP: Pneumocystispneumonia; HIV:human immunodeficiency virus.
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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chest radiographic findings, 6 were finally diagnosed with PCP. In this group, the sensitivity of HRCT was 100% and the specificity was 89% [17]. The typical CT finding in HIV-PCP is bilateral diffuse GGOs, often with a patchy or mosaic pattern, a central distribution, and peripheral sparing (Fig. 1). Atypical radiographic presentations include nodules, cysts, lobar consolidation, upper lobe distribution, and pneumothorax (Figs. 2 and 3).
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Fig. 1 – Computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.)
Fig. 2 – Computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities and multiple nodules. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.)
Fig. 3 – High-resolution computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities with interlobular septal lines and multiple cysts. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.) radiograph taken at the time of presentation occur in up to 39% of patients [16]. High-resolution computed tomography (HRCT) has a higher sensitivity than chest radiography for detecting PCP in HIV-1-infected patients and will often reveal more subtle changes, including faint GGOs. One study reported that among 51 HIV-1-infected patients in whom PCP was suspected despite normal, equivocal, or nonspecific
Serum markers used in the diagnosis of PCP
There are several useful laboratory markers that facilitate the diagnosis of PCP. Of these, serum lactate dehydrogenase (LDH) is highly sensitive and may also have prognostic significance. LDH is elevated in 490% of HIV-PCP. Zaman et al. reported a significantly higher mean LDH level in nonsurvivors of HIV-PCP (447 IU) than in survivors (340 IU) [18,19]. The polysaccharide (1–3)-β-D-glucan (BDG) is a component of the cell wall of fungi, including P. jirovecii. Yasuoka et al. were the first to report high levels of BDG in the serum of patients with PCP [20]. In a study of 282 HIV-PCP by Sax et al., the median plasma BDG level was significantly higher in those with than without PCP (408 vs. 37 pg/mL) [21]. The meta-analysis of Ohnishi et al. revealed the high sensitivity of serum BDG in the diagnosis of PCP [22]. These studies indicate that peripheral measurements of BDG can be very useful in the diagnosis of PCP and that PCP is less likely in patients with a low BDG level. However, BDG is not a specific marker for PCP and its levels may be elevated in patients with other invasive fungal infections and in those who are receiving immunoglobulins, are on hemodialysis, have surgical gauze exposure, or are on certain antibiotics. Koga et al. reported that the serum BDG level does not reflect the severity and prognosis of PCP infection and thus may not to be suitable to be monitored for evaluating the therapeutic response of the PCP treatment [23]. KL-6 antigen, a mucin like glycoprotein expressed on type 2 alveolar pneumocytes, is a potentially useful indicator of interstitial lung disease. Tasaka et al. measured elevated serum levels of KL-6 in patients with PCP [24]. However, KL6 may be a less useful marker than BGD in terms of its diagnostic significance for PCP [25]. Although neither LDH nor BDG nor KL-6 antigen is specific for P. jirovecii, determining the levels of these serum markers may be helpful as an adjunctive test, especially when bronchoscopy cannot be performed, such as in patients with severe respiratory failure.
6.
Definitive diagnosis
Because Pneumocystis cannot be cultured, a histopathologic or cytopathologic demonstration of the organism in sputum or bronchoalveolar lavage (BAL) is required for a definitive diagnosis of PCP. Diagnosis relies on visualizing the cystic or trophic form of the fungus. Sputum induction via inhalation of an aerosol of hypertonic saline is the least invasive method and has a diagnostic yield of 50–90% [26]. Bronchoscopy with BAL alone has a diagnostic yield of 490% [27,28].
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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Table 2 – Treatment of PCP. Preferred therapy
Alternative therapy
Other comments
TMP-SMX: (TMP 15–20 mg and SMX For moderate to severe PCP: Adjunctive corticosteroids: 75–100 mg)/kg/day intravenous or orally, given every 6–8 h Pentamidine 4 mg/kg intravenous once daily Prednisone doses (beginning as early as possible infused over 60 min; can reduce dose to 3 mg/ and within 72 h of PCP therapy) kg intravenous daily because of toxicities, or Days 1–5: 40 mg orally twice daily Primaquine 30 mg (base) daily orally þ clindaDays 6–10: 40 mg orally daily mycin 600 mg every 6 h intravenous, or 900 mg Days 11–21: 20 mg orally daily every 8 h, clindamycin 300 mg orally every 6 Intravenous methylprednisolone can be given as hours, or 450 mg orally every 8 h 75% of prednisone dose Benefit of corticosteroid if started after 72 h of For mild to moderate PCP: Dapson 100 mg daily orally þ TMP 5 mg/kg treatment is unknown, but some clinicians will orally every 8 h, or use it for moderate to severe PCP. Primaquine 30 mg (base) daily orally þ clindamycin 300 mg orally every 6 h, or 450 mg orally every 8 h, or Atovaquone 750 mg orally twice daily with food PCP: Pneumocystis pneumonia; TMP: trimethoprim; SMX: sulfamethoxazole.
The organism can be stained using several techniques. Trophic forms are generally more abundant than cystic forms during PCP and can be detected with Wright-Giemsa and DiffQuik staining. Stains selective for the cell wall of cystic forms are Gomori methenamine silver, toluidine blue O, and cresyl violet. Other agents used in Pneumocystis detection include Papanicolaou and calcofluor white. Indirect immunofluorescent staining of sputum using monoclonal antibodies that react specifically with P. jirovecii has a higher sensitivity (92%) than conventional tinctorial staining (76–80%) [29]. PCR of respiratory samples, such as BAL fluid, induced sputum, and oropharyngeal wash, has a higher sensitivity than histologic staining in the diagnosis of PCP [30]. Although conventional PCR cannot reliably distinguish colonization from disease, negative PCR results may allow for withdrawal of PCP-directed treatment. Quantitative PCR with BAL fluid can be performed to estimate the organism burden, with a larger burden suggesting a higher probability of PCP [31]. In the study of Matsumura et al., the sensitivity and specificity for discriminating definite PCP from colonization were 100% and 80%, respectively, at a cutoff value of 1300 copies/mL [32]. If possible, BAL should be performed in patients with suspected PCP. However, treatment can be initiated before a definitive diagnosis is made, because the causative organism can be stained in BAL specimens for days after treatment initiation.
7.
Disease prevention
HIV-1-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if their CD4 counts are o200 cells/mm3 [33,34]. Those with CD4 cell counts o250 cells/mm3 or o14% are also candidates for prophylaxis against first episodes of PCP [33,34]. Primary PCP prophylaxis should be discontinued in adult and adolescent patients who have responded to ART with an increase in CD4 counts from o200 cells/mm3 to 4200 cells/mm3 for 43 months [33]. One cohort study reported that
HIV-PCP with CD4 counts between 100 and 200 cells/mm3 and an HIV-1 plasma viral load o400 copies/μL who received ART had a low incidence of primary PCP, even though they were not on PCP prophylaxis [35]. Thus, in patients with these clinical features, prophylaxis agents may be safely discontinued at an earlier time point. TMP-SMX is the first recommended prophylactic agent [36– 38]. A single-strength tablet (480 mg) taken daily is as efficacious as a double-strength tablet and may be better tolerated, although one double-strength tablet three times weekly may also be effective [38,39]. However, the incidence of adverse reactions to TMP-SMX is high in HIV-1-infected patients and therapy should be discontinued in those with a lifethreatening adverse reaction, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Other common adverse reactions include fever, leukopenia, thrombocytopenia, azotemia, hepatitis, and hyperkalemia [40]. Patients who previously had an adverse event, such as fever or mild rash, may tolerate a gradual dose escalation of TMP-SMX to a prophylactic dose under careful observation [41,42]. For patients who cannot tolerate TMP-SMX, alternative prophylaxis regimens include dapson, aerosolized pentamidine, and atovaquone. Clinical trials have demonstrated that TMP-SMX is much more effective for prophylaxis than aerosolized pentamidine or dapsoncontaining regimens, whereas atovaquone is as effective as aerosolized pentamidine or dapson [43–45]. Patients who successfully complete PCP treatment also need secondary prophylaxis with TMP-SMX. Alternative regimens include dapson, aerosolized pentamidine, and atovaquone. Secondary prophylaxis should be discontinued in adult and adolescent patients whose CD4 counts have increased from o200 to 4200 cells/mm3 for 43 months as a result of ART.
8.
Treatment
TMP-SMX is the preferred regimen for treating mild to severe PCP in HIV-PCP [46,47]. The standard dose is TMP 15–20 mg
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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and SMX 75–100 mg/kg/day, orally or intravenously, given every 6 or 8 h. In patients who cannot continue TMP-SMX owing to an adverse event, an alternative regimen is generally used. Preferred and alternative regimens are summarized in Table 2. The recommended duration of therapy for HIV-PCP is 21 days, irrespective of the regimen. For patients with mild to moderate disease (defined as PCP associated with room air A-aDO2 o45 mm Hg or a PaO2 Z70 mm Hg), alternative regimens include trimethoprim-dapson, clindamycin-primaquine, or atovaquone. Trimethoprimdapson seems to be as effective as TMP-SMX, but less toxic [47,48]. Clindamycin-primaquine is also effective, but primaquine can only be given orally [49–51]. A large, prospective, double-blind study demonstrated that, whereas atovaquone is less effective than TMP-SMX, it has fewer adverse events [46]. For patients with moderate to severe disease (room air AaDO2 Z 35 mmHg or PaO2 o 70 mmHg), alternative regimens include parenteral pentamidine or clindamycin-primaquine. Parenteral pentamidine is effective for PCP treatment, but adverse reactions are common and can be severe. Nausea, renal dysfunction, cardiac arrhythmias, pancreatitis, hypokalemia, hypocalcemia, hyperglycemia, and hypoglycemia are reported in up to 60% of patients [52]. Caspofungin, one of the echinocandins, targets the synthesis of BDG, a component of the P. jirovecii cell wall. A small retrospective study reported a high success rate in patients receiving caspofungin salvage treatment [53]. Further investigations are needed to ascertain the efficacy of this approach in PCP treatment.
8.1.
Adjunctive corticosteroids
Patients with moderate to severe disease should receive adjunctive corticosteroids as early as possible, and certainly within 72 h after the start of PCP therapy. Patients with PCP typically show clinical worsening after 2–3 days of therapy, presumably due to the increased inflammation induced in response to the dying fungi [54,55]. Corticosteroids may alleviate this response and thus improve the prognosis. A few randomized trials have demonstrated that patients treated with corticosteroids during the treatment of HIVPCP have significantly increased arterial oxygenation and a decreased incidence of respiratory failure and mortality compared with patients who were not treated with corticosteroids, especially those with moderate to severe abnormalities in oxygen exchange at the time of presentation [56–58]. These trials were cited as evidence in the U.S. Centers for Disease Control and Prevention guidelines, which recommend 21-day adjunctive corticosteroid use for HIV-1infected patients with moderate to severe PCP [59].
8.2.
Timing of ART initiation
In most cases of PCP, the patients are not on ART at the time of diagnosis. In a randomized controlled trial of 282 patients with opportunistic infections, 63% of those with PCP were randomized to either the early ART or the deferred ART arm (median of 12 or 45 days, respectively, after the start of opportunistic infection treatment) [60]. Patients in the early arm had a significantly lower incidence of AIDS progression
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and death [60]. There was no associated increase in the frequency of adverse events or immune reconstitution inflammatory syndrome (IRIS). Guidelines generally recommend initiating ART within 2 weeks of PCP diagnosis [59].
8.3.
IRIS associated with PCP
The initiation of ART in HIV-1-infected patients may result in IRIS, an inflammatory disorder associated with paradoxical worsening of preexisting infectious processes. Most cases of IRIS associated with PCP occur within a few weeks after ART initiation. Symptoms include fever, cough, chest discomfort, dyspnea, hypoxia, and a worsening of the chest radiography findings. Although the management of PCP-associated IRIS is not well defined, the prolonged PCP treatment with adjunctive corticosteroids over the treatment course recommended for moderate to severe PCP or the reintroduction of the PCP treatment may be needed for patients who present with respiratory deterioration.
9.
Summary
PCP remains a severe opportunistic infection in HIV-1infected patients, despite the widespread availability of prophylaxis agents and ART. Because Pneumocystis cannot be cultured, a definitive diagnosis of PCP requires visualization of the organism by respiratory specimens. PCR of respiratory specimens and measurements of adjunctive serum biomarkers such as BDG and KL-6 antigen are of relatively high accuracy and may be less invasive diagnostic procedures. However, further evaluation is needed to establish the optimal diagnostic method. TMP-SMX is the first-line regimen in the treatment of PCP. It is highly effective, but the incidence of adverse events is high. Potent and well-tolerated new regimens will need to be developed.
Acknowledgements We thank Dr. Yasuaki Yanagawa (AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan) for allowing us to use chest CT images.
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Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Review
Pneumocystis pneumonia in HIV-1-infected patients Satoshi Shibataa, Toshiaki Kikuchib,n a
Department of Respiratory Medicine, Niigata City General Hospital, Niigata 950-1197, Japan Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachidori, Chuoku, Niigata 951-8510, Japan
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art i cle i nfo
ab st rac t
Article history:
Pneumocystis pneumonia (PCP) is an opportunistic disease that mainly affects patients with
Received 30 October 2018
a deficiency of cell-mediated immunity, especially acquired immunodeficiency syndrome
Received in revised form
(AIDS). The incidence of PCP in these patients has declined substantially owing to the
12 January 2019
widespread use of antiretroviral therapy and PCP prophylaxis. However, PCP is still a major
Accepted 30 January 2019
AIDS-related opportunistic infection, particularly in patients with advanced immunosuppression in whom human immunodeficiency virus type 1 (HIV-1) infection remains undiagnosed or untreated. The clinical manifestations, diagnosis, treatment, and
Keywords:
prevention of PCP in patients with HIV-1 infection are addressed in this review.
Pneumocystis pneumonia Acquired immunodeficiency
& 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
syndrome Human immunodeficiency virus Opportunistic infection
Contents 1. 2. 3. 4. 5. 6. 7. 8.
Biology and epidemiology . . . . . . . . . . . . . . . Transmission . . . . . . . . . . . . . . . . . . . . . . . . . Clinical manifestations . . . . . . . . . . . . . . . . . Radiological findings . . . . . . . . . . . . . . . . . . . Serum markers used in the diagnosis of PCP Definitive diagnosis . . . . . . . . . . . . . . . . . . . . Disease prevention . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abbreviations: A-aDO2, BAL, HRCT, PaO2,
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alveolar-arterial O2 gradient; AIDS,
bronchoalveolar lavage; BDG, (1–3)-β-d-glucan; GGO, high-resolution computed tomography; IRIS, partial pressure of atrial oxygen; PCP,
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acquired immunodeficiency syndrome; ART,
ground-glass opacity; HIV,
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antiretroviral therapy;
human immunodeficiency virus;
immune reconstitution inflammatory syndrome; LDH,
Pneumocystis pneumonia; PCR,
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lactate dehydrogenase;
polymerase chain reaction; SMX,
sulfamethoxazole;
TMP, trimethoprim n Corresponding author. Fax: þ81 25 368 9326. E-mail address: [email protected] (T. Kikuchi). https://doi.org/10.1016/j.resinv.2019.01.009 2212-5345/& 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
8.1. Adjunctive corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Timing of ART initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. IRIS associated with PCP. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.
Biology and epidemiology
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source was postulated. Firas et al. provided quantitative data on the spread of P. jirovecii in the exhaled air from infected patients [14]. The resulting organism burden in air samples decreased with increasing distance from the patient. These data suggested airborne, person-to-person transmission of P. jirovecii from infected patients to immunocompromised hosts. Thus, patients with PCP should not be allowed in the same room as other immunocompromised patients, but data are insufficient to recommend this as a standard practice.
Pneumocystis was identified in 1909 and 1910 by Carlos Chagas and Antonio Carini. Initially, the organism was assumed to be part of the life cycle of Trypanosoma cruzi. However, in 1912, Pneumocystis was recognized as a new genus by Delanoe, who named it Pneumocystis carinii in honor of the work of Antonio Carini [1,2]. Pneumocystis was long thought to be a genus of protozoa, but ribosomal RNA sequencing later revealed it to be a fungus [3]. The nomenclature of Pneumocystis was also changed, from Pneumocystis carinii, which infects rats, to Pneumocystis jirovecii, which infects humans [4]. Despite the passage of more than 100 years since Pneumocystis was first identified, Pneumocystis pneumonia (PCP) was largely unrecognized until the 1980s. In 1981, several young, previously healthy, men who have sex with men were diagnosed with multiple episodes of PCP [5]. This was the first clinical evidence of a disease that would later become known as acquired immunodeficiency syndrome, or AIDS. Its causative agent, the human immunodeficiency virus type 1 (HIV-1), was identified in 1983. Following the onset of the AIDS epidemic, in 1982, there was a marked increase in the incidence of reported cases of PCP. In the late 1980s, an estimated 75% of HIV-1-infected patients had developed PCP [6]. With the introduction of antiretroviral therapy (ART) and chemoprophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX), the incidence of PCP in HIV-1-infected patients has decreased substantially. However, it is still a serious health concern in people living with HIV/AIDS and one of the leading causes of opportunistic infection in this population.
HIV-1-infected patients with PCP (HIV-PCP) typically present with a nonproductive cough, fever, dyspnea, chest discomfort, and malaise that progress over days to weeks. However, up to 7% of these patients can be asymptomatic [15]. By contrast, PCP in non-HIV-1-infected patients (non-HIV-PCP), such as those undergoing anti-malignancy chemotherapy or being treated with immunosuppressive agents, is more likely to be of acute onset and will often cause severe respiratory distress within the first several days. Disease characteristics of HIV-PCP and non-HIV-PCP are summarized in Table 1. Lung auscultation is usually normal, but inspiratory crackles may be detected in some patients. Hypoxemia ranges from mild at room air [partial pressure of atrial oxygen (PaO2) Z70 mm Hg or alveolar-arterial O2 gradient (A-aDO2) o35 mm Hg] to moderate (A-aDO2 Z35 and o45 mm Hg) to severe (A-aDO2 Z45 mm Hg). The approach to treatment is based on the severity of disease and is described below.
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4.
Transmission
The route of Pneumocystis transmission is not well understood. Serologic studies have shown that, by 4 years of age, two-thirds of normal children have antibodies to P. jirovecii [7]. In a nested polymerase chain reaction (PCR) study, Ponce et al. identified P. jirovecii in 64.9% of the autopsied lungs of healthy adults [8]. These findings suggested unapparent infection in the normal population, and in immunocompromised patients, PCP was thought to represent the reactivation of a latent infection. However, an animal study showed the clearance of Pneumocystis after infection, and several possible routes of subsequent transmission were reported [9–12]. Laurence et al. reported that 54% of patients with PCP who were newly diagnosed with HIV-1 and never exposed to sulfa drugs had a mutation in the dihydropteroate synthase (DHPS) gene, which confers resistance to sulfa drugs [13]. Because this mutation is associated with prior exposure to a sulfa drug, recent acquisition of the fungus from an exogenous
3.
Clinical manifestations
Radiological findings
On chest radiography, the most common abnormalities of PCP in both HIV-1-infected and non-HIV-1-infected patients are diffuse bilateral ground-glass opacities (GGOs) or an alveolar pattern. However, normal findings on a chest Table 1 – Characteristics of PCP in HIV-infected and nonHIV-infected patients. HIV-PCP
Non-HIV-PCP
Main symptoms
Fever, shortness of breath, nonproductive cough Severity of symptoms Moderate Severe Onset Subacute Acute Disease course Slow Rapid Progression In weeks In days PCP: Pneumocystispneumonia; HIV:human immunodeficiency virus.
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
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chest radiographic findings, 6 were finally diagnosed with PCP. In this group, the sensitivity of HRCT was 100% and the specificity was 89% [17]. The typical CT finding in HIV-PCP is bilateral diffuse GGOs, often with a patchy or mosaic pattern, a central distribution, and peripheral sparing (Fig. 1). Atypical radiographic presentations include nodules, cysts, lobar consolidation, upper lobe distribution, and pneumothorax (Figs. 2 and 3).
5.
Fig. 1 – Computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.)
Fig. 2 – Computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities and multiple nodules. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.)
Fig. 3 – High-resolution computed tomographic image of Pneumocystis pneumonia, showing diffuse ground-glass opacities with interlobular septal lines and multiple cysts. (Courtesy of Dr. Yasuaki Yanagawa, National Center for Global Health and Medicine, Tokyo, Japan.) radiograph taken at the time of presentation occur in up to 39% of patients [16]. High-resolution computed tomography (HRCT) has a higher sensitivity than chest radiography for detecting PCP in HIV-1-infected patients and will often reveal more subtle changes, including faint GGOs. One study reported that among 51 HIV-1-infected patients in whom PCP was suspected despite normal, equivocal, or nonspecific
Serum markers used in the diagnosis of PCP
There are several useful laboratory markers that facilitate the diagnosis of PCP. Of these, serum lactate dehydrogenase (LDH) is highly sensitive and may also have prognostic significance. LDH is elevated in 490% of HIV-PCP. Zaman et al. reported a significantly higher mean LDH level in nonsurvivors of HIV-PCP (447 IU) than in survivors (340 IU) [18,19]. The polysaccharide (1–3)-β-D-glucan (BDG) is a component of the cell wall of fungi, including P. jirovecii. Yasuoka et al. were the first to report high levels of BDG in the serum of patients with PCP [20]. In a study of 282 HIV-PCP by Sax et al., the median plasma BDG level was significantly higher in those with than without PCP (408 vs. 37 pg/mL) [21]. The meta-analysis of Ohnishi et al. revealed the high sensitivity of serum BDG in the diagnosis of PCP [22]. These studies indicate that peripheral measurements of BDG can be very useful in the diagnosis of PCP and that PCP is less likely in patients with a low BDG level. However, BDG is not a specific marker for PCP and its levels may be elevated in patients with other invasive fungal infections and in those who are receiving immunoglobulins, are on hemodialysis, have surgical gauze exposure, or are on certain antibiotics. Koga et al. reported that the serum BDG level does not reflect the severity and prognosis of PCP infection and thus may not to be suitable to be monitored for evaluating the therapeutic response of the PCP treatment [23]. KL-6 antigen, a mucin like glycoprotein expressed on type 2 alveolar pneumocytes, is a potentially useful indicator of interstitial lung disease. Tasaka et al. measured elevated serum levels of KL-6 in patients with PCP [24]. However, KL6 may be a less useful marker than BGD in terms of its diagnostic significance for PCP [25]. Although neither LDH nor BDG nor KL-6 antigen is specific for P. jirovecii, determining the levels of these serum markers may be helpful as an adjunctive test, especially when bronchoscopy cannot be performed, such as in patients with severe respiratory failure.
6.
Definitive diagnosis
Because Pneumocystis cannot be cultured, a histopathologic or cytopathologic demonstration of the organism in sputum or bronchoalveolar lavage (BAL) is required for a definitive diagnosis of PCP. Diagnosis relies on visualizing the cystic or trophic form of the fungus. Sputum induction via inhalation of an aerosol of hypertonic saline is the least invasive method and has a diagnostic yield of 50–90% [26]. Bronchoscopy with BAL alone has a diagnostic yield of 490% [27,28].
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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Table 2 – Treatment of PCP. Preferred therapy
Alternative therapy
Other comments
TMP-SMX: (TMP 15–20 mg and SMX For moderate to severe PCP: Adjunctive corticosteroids: 75–100 mg)/kg/day intravenous or orally, given every 6–8 h Pentamidine 4 mg/kg intravenous once daily Prednisone doses (beginning as early as possible infused over 60 min; can reduce dose to 3 mg/ and within 72 h of PCP therapy) kg intravenous daily because of toxicities, or Days 1–5: 40 mg orally twice daily Primaquine 30 mg (base) daily orally þ clindaDays 6–10: 40 mg orally daily mycin 600 mg every 6 h intravenous, or 900 mg Days 11–21: 20 mg orally daily every 8 h, clindamycin 300 mg orally every 6 Intravenous methylprednisolone can be given as hours, or 450 mg orally every 8 h 75% of prednisone dose Benefit of corticosteroid if started after 72 h of For mild to moderate PCP: Dapson 100 mg daily orally þ TMP 5 mg/kg treatment is unknown, but some clinicians will orally every 8 h, or use it for moderate to severe PCP. Primaquine 30 mg (base) daily orally þ clindamycin 300 mg orally every 6 h, or 450 mg orally every 8 h, or Atovaquone 750 mg orally twice daily with food PCP: Pneumocystis pneumonia; TMP: trimethoprim; SMX: sulfamethoxazole.
The organism can be stained using several techniques. Trophic forms are generally more abundant than cystic forms during PCP and can be detected with Wright-Giemsa and DiffQuik staining. Stains selective for the cell wall of cystic forms are Gomori methenamine silver, toluidine blue O, and cresyl violet. Other agents used in Pneumocystis detection include Papanicolaou and calcofluor white. Indirect immunofluorescent staining of sputum using monoclonal antibodies that react specifically with P. jirovecii has a higher sensitivity (92%) than conventional tinctorial staining (76–80%) [29]. PCR of respiratory samples, such as BAL fluid, induced sputum, and oropharyngeal wash, has a higher sensitivity than histologic staining in the diagnosis of PCP [30]. Although conventional PCR cannot reliably distinguish colonization from disease, negative PCR results may allow for withdrawal of PCP-directed treatment. Quantitative PCR with BAL fluid can be performed to estimate the organism burden, with a larger burden suggesting a higher probability of PCP [31]. In the study of Matsumura et al., the sensitivity and specificity for discriminating definite PCP from colonization were 100% and 80%, respectively, at a cutoff value of 1300 copies/mL [32]. If possible, BAL should be performed in patients with suspected PCP. However, treatment can be initiated before a definitive diagnosis is made, because the causative organism can be stained in BAL specimens for days after treatment initiation.
7.
Disease prevention
HIV-1-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if their CD4 counts are o200 cells/mm3 [33,34]. Those with CD4 cell counts o250 cells/mm3 or o14% are also candidates for prophylaxis against first episodes of PCP [33,34]. Primary PCP prophylaxis should be discontinued in adult and adolescent patients who have responded to ART with an increase in CD4 counts from o200 cells/mm3 to 4200 cells/mm3 for 43 months [33]. One cohort study reported that
HIV-PCP with CD4 counts between 100 and 200 cells/mm3 and an HIV-1 plasma viral load o400 copies/μL who received ART had a low incidence of primary PCP, even though they were not on PCP prophylaxis [35]. Thus, in patients with these clinical features, prophylaxis agents may be safely discontinued at an earlier time point. TMP-SMX is the first recommended prophylactic agent [36– 38]. A single-strength tablet (480 mg) taken daily is as efficacious as a double-strength tablet and may be better tolerated, although one double-strength tablet three times weekly may also be effective [38,39]. However, the incidence of adverse reactions to TMP-SMX is high in HIV-1-infected patients and therapy should be discontinued in those with a lifethreatening adverse reaction, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Other common adverse reactions include fever, leukopenia, thrombocytopenia, azotemia, hepatitis, and hyperkalemia [40]. Patients who previously had an adverse event, such as fever or mild rash, may tolerate a gradual dose escalation of TMP-SMX to a prophylactic dose under careful observation [41,42]. For patients who cannot tolerate TMP-SMX, alternative prophylaxis regimens include dapson, aerosolized pentamidine, and atovaquone. Clinical trials have demonstrated that TMP-SMX is much more effective for prophylaxis than aerosolized pentamidine or dapsoncontaining regimens, whereas atovaquone is as effective as aerosolized pentamidine or dapson [43–45]. Patients who successfully complete PCP treatment also need secondary prophylaxis with TMP-SMX. Alternative regimens include dapson, aerosolized pentamidine, and atovaquone. Secondary prophylaxis should be discontinued in adult and adolescent patients whose CD4 counts have increased from o200 to 4200 cells/mm3 for 43 months as a result of ART.
8.
Treatment
TMP-SMX is the preferred regimen for treating mild to severe PCP in HIV-PCP [46,47]. The standard dose is TMP 15–20 mg
Please cite this article as: Shibata S, Kikuchi T. Pneumocystis pneumonia in HIV-1-infected patients. Respiratory Investigation (2019), https://doi.org/10.1016/j.resinv.2019.01.009
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and SMX 75–100 mg/kg/day, orally or intravenously, given every 6 or 8 h. In patients who cannot continue TMP-SMX owing to an adverse event, an alternative regimen is generally used. Preferred and alternative regimens are summarized in Table 2. The recommended duration of therapy for HIV-PCP is 21 days, irrespective of the regimen. For patients with mild to moderate disease (defined as PCP associated with room air A-aDO2 o45 mm Hg or a PaO2 Z70 mm Hg), alternative regimens include trimethoprim-dapson, clindamycin-primaquine, or atovaquone. Trimethoprimdapson seems to be as effective as TMP-SMX, but less toxic [47,48]. Clindamycin-primaquine is also effective, but primaquine can only be given orally [49–51]. A large, prospective, double-blind study demonstrated that, whereas atovaquone is less effective than TMP-SMX, it has fewer adverse events [46]. For patients with moderate to severe disease (room air AaDO2 Z 35 mmHg or PaO2 o 70 mmHg), alternative regimens include parenteral pentamidine or clindamycin-primaquine. Parenteral pentamidine is effective for PCP treatment, but adverse reactions are common and can be severe. Nausea, renal dysfunction, cardiac arrhythmias, pancreatitis, hypokalemia, hypocalcemia, hyperglycemia, and hypoglycemia are reported in up to 60% of patients [52]. Caspofungin, one of the echinocandins, targets the synthesis of BDG, a component of the P. jirovecii cell wall. A small retrospective study reported a high success rate in patients receiving caspofungin salvage treatment [53]. Further investigations are needed to ascertain the efficacy of this approach in PCP treatment.
8.1.
Adjunctive corticosteroids
Patients with moderate to severe disease should receive adjunctive corticosteroids as early as possible, and certainly within 72 h after the start of PCP therapy. Patients with PCP typically show clinical worsening after 2–3 days of therapy, presumably due to the increased inflammation induced in response to the dying fungi [54,55]. Corticosteroids may alleviate this response and thus improve the prognosis. A few randomized trials have demonstrated that patients treated with corticosteroids during the treatment of HIVPCP have significantly increased arterial oxygenation and a decreased incidence of respiratory failure and mortality compared with patients who were not treated with corticosteroids, especially those with moderate to severe abnormalities in oxygen exchange at the time of presentation [56–58]. These trials were cited as evidence in the U.S. Centers for Disease Control and Prevention guidelines, which recommend 21-day adjunctive corticosteroid use for HIV-1infected patients with moderate to severe PCP [59].
8.2.
Timing of ART initiation
In most cases of PCP, the patients are not on ART at the time of diagnosis. In a randomized controlled trial of 282 patients with opportunistic infections, 63% of those with PCP were randomized to either the early ART or the deferred ART arm (median of 12 or 45 days, respectively, after the start of opportunistic infection treatment) [60]. Patients in the early arm had a significantly lower incidence of AIDS progression
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and death [60]. There was no associated increase in the frequency of adverse events or immune reconstitution inflammatory syndrome (IRIS). Guidelines generally recommend initiating ART within 2 weeks of PCP diagnosis [59].
8.3.
IRIS associated with PCP
The initiation of ART in HIV-1-infected patients may result in IRIS, an inflammatory disorder associated with paradoxical worsening of preexisting infectious processes. Most cases of IRIS associated with PCP occur within a few weeks after ART initiation. Symptoms include fever, cough, chest discomfort, dyspnea, hypoxia, and a worsening of the chest radiography findings. Although the management of PCP-associated IRIS is not well defined, the prolonged PCP treatment with adjunctive corticosteroids over the treatment course recommended for moderate to severe PCP or the reintroduction of the PCP treatment may be needed for patients who present with respiratory deterioration.
9.
Summary
PCP remains a severe opportunistic infection in HIV-1infected patients, despite the widespread availability of prophylaxis agents and ART. Because Pneumocystis cannot be cultured, a definitive diagnosis of PCP requires visualization of the organism by respiratory specimens. PCR of respiratory specimens and measurements of adjunctive serum biomarkers such as BDG and KL-6 antigen are of relatively high accuracy and may be less invasive diagnostic procedures. However, further evaluation is needed to establish the optimal diagnostic method. TMP-SMX is the first-line regimen in the treatment of PCP. It is highly effective, but the incidence of adverse events is high. Potent and well-tolerated new regimens will need to be developed.
Acknowledgements We thank Dr. Yasuaki Yanagawa (AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan) for allowing us to use chest CT images.
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