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Role of Plasmapheresis and Extracorporeal Membrane Oxygenation in the Treatment of Leptospirosis Complicated with Pulmonary Hemorrhages.

1. Background

Leptospirosis is an emerging infectious disease with increasing incidence in both developing and developed countries [1]. It has a wide geographical distribution and is observed commonly in tropical, subtropical, and temperate zones, reaching endemic proportions in South East Asian region [2]. Globally, around 10,000 severe cases of leptospirosis require hospitalization every year [1]. The major burden attributed to leptospirosis has been the severe life-threatening manifestations. Leptospirosis has a mean case fatality ratio of 6.85%, with the highest risk for death among males of 50-59 years of age [3]. Of the disease related complications, pulmonary hemorrhages are the major cause of mortality, accounting for 30-60% of deaths [4-8]. Edilane L et al. have reported an increasing detection rate of pulmonary hemorrhages in Brazil in the recent past [9].

Antibiotics are the mainstay of treatment in suspected or confirmed leptospirosis but the efficacy of different antibiotics is uncertain due to the scarcity of clinical trials [10]. In pulmonary involvement where the highest mortality is seen, there is sparse evidence for an effective treatment modality, currently. Although high-dose intravenous glucocorticoids are used in pulmonary involvement, the evidence is weak and is limited to case reports and case series [11]. Clinical trials [12, 13] have shown that glucocorticoids are ineffective and may increase the risk of nosocomial infections. Intravenous cyclophosphamide has been found to be effective in a single nonrandomized trial conducted in India, but the methodological flaws seen in this study restrict the application of the results in patient care [14].

There is a growing interest in plasmapheresis and ECMO as potential treatment modalities for leptospirosis with lung involvement. These treatment modalities require additional resources such as expertise and infrastructure; hence, they are not widely used. Plasmapheresis and ECMO, however, have not been included in the national patient management guidelines in countries where the condition is prevalent. We intended to explore the effectiveness of plasmapheresis or ECMO in a systematic manner using the current evidence.

2. Methods

The review was done adhering to the PRISMA protocol. The first search was conducted in PubMed using keywords "leptospirosis" OR "Leptospira" OR "Weil's disease" AND

"plasmapheresis" OR "plasma exchange" AND "pulmonary haemorrhage" OR "alveolar haemorrhage" OR "lung haemorrhage" and the second search was done with keywords "leptospirosis" OR "Leptospira" OR "Weil's disease" AND "ECMO" OR "Extracorporeal membrane oxygenation." Last search was done on September 20, 2018 (Figures 1 and 2). The searches were not limited by study design or the date of publication. Only articles written in English were reviewed. One article that did not have an English translation was excluded. A similar search was conducted on OVID, Google Scholar, and the Cochrane clinical trial registry. Although our initial intention was to include only clinical trials, we decided to include other forms of information such as case reports and case series, which addressed plasmapheresis or ECMO in leptospirosis. Other types of publications such as reviews and comments were excluded. Reference lists of included articles were also perused. No additional eligible articles were found. Two authors selected articles independently in a blinded manner using a set of inclusion and exclusion criteria and discrepancies were sorted out after discussion.

3. Results

3.1. Evidence on Plasmapheresis for Patients with Leptospirosis Pulmonary Hemorrhage (Table 1). We found two case reports [15, 16] and one clinical trial [17], where benefits of plasmapheresis in severe leptospirosis with pulmonary hemorrhages have been described. Chen et al. [15] described a patient with leptospirosis and coinfection with typhus presenting with diffuse alveolar hemorrhage and acute kidney injury (AKI) and recovered after 8 cycles of plasma exchange and high-dose steroids. Despite recovery from pulmonary hemorrhage, this patient had a complicated course of illness with active gastrointestinal bleeding and necessitated 6 weeks of hospitalization. Dursan B et al. [16] have described a patient with severe alveolar hemorrhages and AKI following leptospirosis and recovered after 9 cycles of plasmapheresis. Trivedi et al. [17] described a nonrandomized trial in which first 30 patients received conventional therapy with antibiotics and steroids and next consecutive 114 patients received plasmapheresis and cyclophosphamide. This study showed a high mortality benefit in the plasmapheresis group when compared with the conventional treatment (61.4% vs 16.6%). The study only recruited patients with mild pulmonary hemorrhages with an acute lung injury score less than 25 and there were limitations in the study design.

3.2. Evidence on Extracorporeal Membrane Oxygenation for Patients with Leptospirosis Pulmonary Hemorrhage (Table 2). There were eight case reports and one retrospective study where ECMO is used in patient with leptospirosis with pulmonary hemorrhage [25-33]. Seven case reports [25-31] showed benefits of ECMO in patients with leptospirosis while one report [32] described treatment failure despite using variety of advanced invasive treatment measures. Also, in a retrospective study of 134 leptospirosis cases treated in ICU, five have undergone ECMO, out of which four have survived [33]. In individual case reports, Pardinas et al. [25] described a patient presenting with massive hemoptysis and persistently low oxygenation despite ventilation, recovering after 18 days of venovenous ECMO (vv-ECMO). This patient has received concurrent aminocaproic acid infusion to reduce pulmonary bleeding. Liao et al. [26] describe a patient with severe leptospirosis complicated by massive pulmonary hemorrhage with fresh bleeding from endotracheal tube leading to refractory hypoxemia and hypercapnia despite ventilation recovering after 6 days of vv-ECMO. A 50-year-old patient who had leptospiremic septic shock with acute respiratory failure underwent vv-ECMO where higher blood flow rates were used with a lower activated partial thromboplastin time (40-50sec) due to the bleeding in the initial three days. He recovered after 11 days of ECMO despite being complicated with acute kidney injury (AKI) requiring renal replacement therapy and cardiomyopathy with an ejection fraction of 30% [27]. A patient who had a sudden cardiac arrest due to severe hypoxemia subsequent to lung haemorrhage recovered after 183 hours of ECMO [28]. This patient required molecular adsorption recycling system (MARS) in order to reduce hyperbilirubinemia. Cantwell et al. describe an obese 39year-old patient with lung hemorrhage requiring vv-ECMO with a second membrane oxygenator to improve oxygenation to maintain enough membrane surface and flow due to obesity [29]. Another traveller from Laos recovered after being on ECMO for 9 days [30].

Except in one instance where venoarterial ECMO was used [31], all have used vv-ECMO. There was one report where a patient presenting with established multiorgan failure underwent ventilation, plasmapheresis, vv-ECMO, and continuous renal replacement therapy (CRRT) with extracorporeal cytokine absorbent therapy but, despite all measurements, the patient succumbed [32].

3.3. Evidence of Plasmapheresis for Leptospirosis Where Pulmonary Hemorrhage Was Not Either Present or Clearly Mentioned (Table 1). In some instances, plasmapheresis has been used in situations where pulmonary hemorrhage was not either present or clearly mentioned and they too failed to show a clear treatment benefit. Landini et al. summarized 6 patients with hyperbilirubinemia, AKI, and no-specified hemorrhagic manifestations treated with plasmapheresis and noticed an improvement of hepatorenal function and bleeding [18]. Another patient with AKI and liver and cardiac involvement but without pulmonary involvement has been treated with plasmapheresis combined with continuous renal replacement therapy and high-volume hemofiltration but subsequently developed CMV colitis and resistant bacteremia and required prolonged hospital stay and was released from hospital after 70 days [19]. Another patient with multiorgan involvement (cardiac, renal, and hepatic involvement) and hemoptysis recovered following plasma exchange and systemic steroid therapy [20]. There were two case reports where plasma exchange was performed to reduce the toxic effects of hyperbilirubinemia with the intention of reducing its toxic effects on tissues including kidneys [21, 22]. In both these instances, there was a marked reduction of bilirubin levels by plasma exchange and both these patients had diffuse pulmonary infiltrates in chest radiography and they were not clearly mentioned as pulmonary hemorrhages. There is a case report and a case series where multiorgan involvement was present and plasma exchange was used with continuous venovenous hemofiltration (CVVHF) to assist recovery [23, 24].

4. Discussion

In this systematic review, we found no strong evidence to support the routine use of plasmapheresis or plasma exchange in leptospirosis complicated with pulmonary hemorrhage. Current evidence is limited to several case reports and a solitary no-randomized clinical trial. Case reports have inherited publication bias, since treatment failures are unlikely to be reported. The only clinical trial on plasmapheresis is nonrandomized, used patients with mild lung involvement, and used cyclophosphamide as an adjuvant therapy. Furthermore, as the two groups were nonparallel, the type of care provided to them could have been different. Also, the mortality benefits in the intervention group are surprisingly more significant than in the control group. It can be argued that the experience gathered in treating controls first may have helped to provide an improved care for the treatment group subsequently.

The frameworks for using ECMO or plasmapheresis are fundamentally different. Plasmapheresis could be considered a treatment targeting pathogenesis of the disease which may help to remove offending antibodies and immune complexes. But it may be hazardous in inducing dilutional coagulopathy and there is a possibility that protective coagulation factors can be removed during the process. Also, there are concerns that exposure to blood products can lead to critical hemodynamic compromise by giving rise to anaphylaxis. On the other hand, patients with very severe diseases may succumb as the effects of plasmapheresis may not occur immediately as they do not correct the hypoxemia due to the acute respiratory failure. Conversely, ECMO is a symptomatic treatment of respiratory failure, which corrects the persistent hypoxemia, which can lead to multiorgan dysfunction. Its use is more recent than for plasmapheresis and tends to increase (4 articles in 2017), gaining a significant interest in leptospirosis associated pulmonary hemorrhage. In severe cases of lung hemorrhage, experts prefer using ECMO due to the mentioned reasons, especially when the lung involvement is isolated or predominant. Interestingly, although these techniques were previously reserved for developed countries, now their use is spreading in some developing countries (Southeast Asia), especially endemic to leptospirosis.

Another symptomatic treatment was aminocaproic acid [34, 35] to reduce bleeding from lungs and inhaled nitric oxide [36] which has been known to increase pulmonary blood flow to areas of normal ventilation and DDAVP [13, 37]. Desmopressin is known to trigger the release of endothelial haemostatic factors, shortens prolonged bleeding times, enhances platelet adhesiveness, and induces von Willebrand factor secretion by activating endothelial cell V2 receptors. Also, desmopressin has also been proven to be effective in the bleeding associated with hepatic and renal failure [13]. Although in a case series of 6 patients cessation of bleeding was demonstrated with DDAVP [37], a randomized control study of DDAVP disproves this by showing no significant difference compared with the control or steroid treatment groups [13]. Surprisingly, we could not find evidence on using tranexamic acid in leptospirosis pulmonary hemorrhages.

The current National guidelines on leptospirosis in India and Sri Lanka only recommend antibiotics, high-dose corticosteroids, and respiratory support when the disease is complicated with pulmonary hemorrhage. The latest Indian guidelines developed in 2015 have not included plasmapheresis as a treatment option, although the results of the clinical trial by Trivedi et al. were available by then. This is understandable as the treatment benefit shown in this study has not been confirmed by other workers.

We found four case reports [38-41] to support the recommendations made by the national guidelines of Sri Lanka and India [42, 43]. These patients with severe pulmonary hemorrhages were only treated with high-dose corticosteroids and respiratory support and they have recovered fully. In some instances patients have recovered with respiratory support without corticosteroids [44-48].

Lack of evidence, however, is not synonymous with lack of efficacy and it calls for methodologically sound well-conducted clinical trials. Leptospirosis is prevalent in tropical, subtropical, and especially South Asian regions, where clinical trials are infrequent. Financial constraints and lack of resources do not provide an environment conducive for clinical trials in this region. Despite these limitations, urgent attention should be paid to this deadly disease and more clinical trials should be conducted to minimize the high mortality currently seen.

5. Conclusion

Current available evidence is insufficient to recommend the routine use of ECMO, plasmapheresis, or plasma exchange for patients presenting with pulmonary hemorrhages due to leptospirosis. These advanced modes of treatment, however, can be applied based on the availability of resources and expertise locally, at the discretion of the clinician in charge, considering each patient individually.

https://doi.org/10.1155/2018/4520185

Data Availability

All details are included in this published article and are available from included studies which are fully referenced.

Ethical Approval

No ethical approval was sought as it was deemed unnecessary for this systematic review.

Disclosure

C. L. Fonseka is a Consultant Physician in Internal Medicine, University Medical Unit, Faculty of Medicine, University of Ruhuna. S. Lekamwasam is the Professor of Medicine, Department of Internal Medicine, University Medical Unit, Faculty of Medicine, University of Ruhuna.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

C. L. Fonseka and S. Lekamwasam individually performed the search in the databases and selected articles based on their titles and abstracts and selected the studies included in the review based on a full-text analysis and wrote the critical revision of the manuscript content. All authors read and approved the final manuscript.

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C. L. Fonseka (iD), S. Lekamwasam (iD)

Department of Internal Medicine, Faculty of Medicine, University of Ruhuna, Sri Lanka

Correspondence should be addressed to C. L. Fonseka; lakmalfonseka@med.ruh.ac.lk

Received 23 August 2018; Revised 24 September 2018; Accepted 10 October 2018; Published 2 December 2018

Academic Editor: Pedro P. Chieffi

Caption: Figure 1: Plasma exchange (last search September 30, 2018).

Caption: Figure 2: Extracorporeal membrane oxygenation (last search September 30, 2018).
Table 1: Summary table for leptospirosis patients treated with
plasmapheresis. PEX for patients with leptospirosis related
pulmonary hemorrhages

Reference              Level of evidence      Complications of
                                              disease

Chen Y et al [15]      Case report-           Pulmonary
                       coinfection with       hemorrhage, acute
                       scrub typhus           renal failure

Dursun B et al [16]    Case report            Pulmonary hemorrhage,
                                              renal failure

                       Nonrandomized          Only mild cases
Trivedi SV et al       nonparallel clinical   (ALI score <2.5)
[17]                   trial, 2 groups        were included
                       sequentially
                       recruited

PEX when pulmonary hemorrhage was not present or not clearly
mentioned

Landini et al [18]     Case series of 6       Hyperbilirubinemia
                       patients               and hemorrhagic
                                              manifestations
                                              (not specified)

Bourquin V et al       Case report            Multiorgan
[19]                                          dysfunction (acute
                                              kidney injury, liver
                                              failure,
                                              myocarditis,
                                              thrombocytopenia)

Taylor et al [20]      Case report            Multiorgan
                                              dysfunction
                                              (hemoptysis with
                                              acute respiratory
                                              failure, marked
                                              hyperbilirubinemia
                                              with fulminant liver
                                              failure, AKI, AF,
                                              shock)

Tse KC et al [21]      Case report            Severe conjugated
                                              hyperbilirubinemia
                                              with liver failure,
                                              acute renal failure,
                                              CXR -diffuse
                                              bilateral pulmonary
                                              infiltrates

Cerdas-Quesada C et    Case report            Hyperbilirubinemia,
al [22]                                       liver failure, acute
                                              kidney injury, CXR -
                                              diffuse bilateral
                                              pulmonary
                                              infiltrates

Yesilbas O et al       Case report            Cardiac arrest,
[23]                                          pericardial
                                              tamponade, renal
                                              failure, macrophage
                                              activation syndrome,
                                              later suffered
                                              prolonged jaundice
                                              and sclerosing
                                              cholangitis

Siriwanij T et al      Case series            10 patients' lung
[24]                                          crepitations, 2
                                              patients had
                                              hemoptysis,
                                              hyperbilirubinemia,
                                              transaminitis, renal
                                              failure

Reference              Treatment used         Other complications

Chen Y et al [15]      8 cycles PEX and       Active upper
                       corticosteroids        gastrointestinal
                                              bleeding

Dursun B et al [16]    9 PEX,
                       corticosteroids

Trivedi SV et al       PEX
[17]

PEX when pulmonary hemorrhage was not present or not clearly
mentioned

Landini et al [18]     PEX

Bourquin V et al       PEX, CRRT,             Penicillin-
[19]                   high-volume            resistant
                       hemofiltration         enterococcus
                       (HVHF)                 bacteremia, dry
                                              necrosis of both
                                              extremities,
                                              transient pacing,
                                              several respiratory
                                              arrests, severe CMV
                                              colitis requiring
                                              sigmoidectomy and
                                              ganciclovir

Taylor et al [20]

                       2 PEX, CRRT,
                       corticosteroids

Tse KC et al [21]

                       PEX

Cerdas-Quesada C et
al [22]                5 PEX

Yesilbas O et al
[23]                   PEX, continuous
                       ven oven ous
                       hemofiltration
                       (CWHF)

Siriwanij T et al      PEX or continuous
[24]                   ven oven ous
                       hemofiltration
                       (CWH)

Reference              Outcome

Chen Y et al [15]      Discharged after 6
                       weeks of
                       hospitalization

Dursun B et al [16]    Recovered

                       Control group--5/30
Trivedi SV et al       patients (16.6%)
[17]                   survived Treatment
                       group//PEX & CPP 70/
                       114 patients (61.4%)
                       survived

PEX when pulmonary hemorrhage was not present or not clearly
mentioned

Landini et al [18]     Improvement of
                       hepatorenal
                       function,
                       hemorrhagic state
                       and coma grade

Bourquin V et al       ICU 45 days and
[19]                   discharged after
                       70 days

Taylor et al [20]      Recovered. CRRT
                       stopped after 9 days

Tse KC et al [21]

                       Recovered

Cerdas-Quesada C et
al [22]                Recovered

Yesilbas O et al       Recovered,
[23]                   transferred to ward
                       after 62 days in ICU

Siriwanij T et al
[24]                   All recovered

* PEX: plasma exchange, ALI: acute ling injury, CRRT: continuous
renal replacement therapy, ICU: intensive care unit.

Table 2: Summary table for leptospirosis pulmonary hemorrhage
(PH) patients treated with ECMO.

Author                 Level of evidence      Reason to initiate
                                              ECMO

Pardinas M et al       Case report            Massive hemoptysis
[25]                                          and acute hypoxemic
                                              respiratory failure
                                              (after 36 h of
                                              arrival)

Liao CY et al [26]     Case report            Refractory acute
                                              respiratory failure,
                                              severe hypercapnia,
                                              continuous bleeding
                                              from ET

Umei N et al [27]      Case report            Pulmonary hemorrhage

Arokianathan           Case report            Pulmonary hemorrhage
D et al [28]                                  with progressively
                                              decreasing oxygen
                                              saturations, 300 ml
                                              of fresh blood from
                                              endotracheal tube

Cantwell T et al       Case report            Pulmonary hemorrhage
[29]

Hery G et al [30]      Case report            Pulmonary hemorrhage
                                              with massive
                                              hemoptysis

Kahn MJ et al [31]     Case report            Pulmonary hemorrhage
                                              with progressive
                                              hypoxia

Ludwig et al [32]      Case report            Pulmonary hemorrhage

Delmas B et            Retrospective study
al [33]                of 134 ICU
                       leptospirosis
                       admissions

Author                 Respiratory settings   Advanced treatment
                       recorded before ECMO   modalities

Pardinas M et al       Pao2-Fio2 ratio (P-    vv-ECMO (13 days),
[25]                   F) <30 mm Hg and       Aminocaproic acid
                       plateau pressures      infusion
                       >40 cm-H20, Sp02 74-
                       80% (ACT -160-180
                       seconds due to
                       persistent
                       hemoptysis)

Liao CY et al [26]     Pao2/Fio2 ratio (P/    Venous ECMO (6 days)
                       F)--163, p02 of 65.5
                       mmHg and pC02 of
                       78.1 mmHg and Fi02
                       of 40%

Umei N et al [27]      Fi02--100%, pa02 -     vv-ECMO (11 days)
                       70.4mmHg, paC02 -
                       28.3mmHg, PEEP -10
                       cm H20

Arokianathan           Fi02 100%, pa02-       vv-ECMO (183 hrs),
D et al [28]           7.7kPa, pC02--         molecular adsorption
                       5.1kPa                 recycling system
                                              (MARS) for
                                              hyperbilirubinemia

Cantwell T et al       Pa02/Fi02--89,         vv-ECMO (8 days),
[29]                   Murray score 3         high-volume
                                              hemofiltration
                                              (HVHF), high flow
                                              with 2 oxygenators
                                              (as the patient is
                                              obese)

Hery G et al [30]      Pa02: Fi02 ratio--     vv-ECMO (9 days)
                       34, Fi02100%, and
                       PEEP of 10 cm h2o.

Kahn MJ et al [31]                            Venoarterial ECMO
                                              (60 hrs)

Ludwig et al [32]      p02 51.8 mmHg, pC02    vv-ECMO, PEX, CRRT,
                       60.8mmHg, Sp02 60%     extracorporeal
                       on air                 cytokine absorbent
                                              therapy

Delmas B et
al [33]                Median Pao2-Fio2
                       ratio -155 (85-211)
                       for the 14 patients
                       (10%) undergoing
                       ventilation

Author                 Day of PH    Complications

Pardinas M et al       D12          Episodic
[25]                                hypotension, AKI on
                                    RRT, multiorgan
                                    failure

Liao CY et al [26]     D3           No RRT (creatinine
                                    1.6mg/dl), shock

Umei N et al [27]      D5           Septic shock AKI on
                                    RRT, myocarditis

Arokianathan
D et al [28]           D5           AKI, hyperbilirubinemia,
                                    cardiac arrest

Cantwell T et al                    AKI, septic shock
[29]                                ARDS, myocarditis

Hery G et al [30]                   Shock disseminated
                                    intravascular
                                    coagulation, AKI,
                                    lactic acidosis

Kahn MJ et al [31]     D3           Septic shock,
                                    myocarditis, atrial
                                    fibrillation, AKI on
                                    RRT

Ludwig et al [32]      D1           AKI on RRT, septic
                                    shock, ARDS
                                    intravascular
                                    hemolysis (TTP DIC
                                    excluded) Overall
                                    mortality rate was
                                    6%, mortality in
                                    moderate-to-severe

Delmas B et                         ARDS subgroup was
al [33]                             25%, four patients
                                    died from refractory
                                    ARDS (one with
                                    therapeutic
                                    limitations), three
                                    from multiple organ
                                    failure, and one
                                    from nosocomial
                                    septic shock

Author                 Outcome

Pardinas M et al       Discharged after 40
[25]                   days

Liao CY et al [26]     Discharged after 10
                       days

Umei N et al [27]      Recovered. Extubated
                       on day 13

Arokianathan
D et al [28]           Recovery

Cantwell T et al       Discharged on day 28
[29]

Hery G et al [30]      Discharged after 20
                       days

Kahn MJ et al [31]     Discharged on day 26

Ludwig et al [32]      Died 29 hrs after
                       initial symptoms (17
                       hrs after admission)

Delmas B et            Five patients who
al [33]                underwent ECMO for
                       refractory ARDS, 80%
                       (4 patients)
                       survived

* ECMO: extracorporeal membrane oxygenation, ACT: activated clotting
time, AKI: acute kidney injury, RRT: renal replacement therapy,
PEX: plasma exchange, CRRT: continuous renal replacement therapy,
ARDS: acute respiratory distress syndrome, ICU: intensive care unit.
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Author:Fonseka, C.L.; Lekamwasam, S.
Publication:Journal of Tropical Medicine
Article Type:Report
Date:Jan 1, 2018
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