Preferred specimens for diagnosis according the histoplasmosis syndromes [1, 2].
\r\n\tIt is a relatively simple process and a standard tool in any industry. Because of the versatility of the titration techniques, nearly all aspects of society depend on various forms of titration to analyze key chemical compounds.
\r\n\tThe aims of this book is to provide the reader with an up-to-date coverage of experimental and theoretical aspects related to titration techniques used in environmental, pharmaceutical, biomedical and food sciences.
Histoplasmosis caused by Histoplasma capsulatum leads to a wide spectrum of symptomatology [1, 2, 3] varying from subclinical or acute to chronic form. Histoplasmosis can be localized or it causes a disseminated, life-threatening infection involving various tissues and organs of the body, notably in immunocompromised hosts [1, 4].
This is a thermally dimorphic fungus presenting as a yeast at body temperature and as a hyaline mold in the natural environment. Human histoplasmosis is due to the two varieties of the pathogen: H. capsulatum var. capsulatum (Hcc) and H. capsulatum var. duboisii (Hcd), which could be distinguished by their epidemiology, their clinical presentation, and the morphological aspect of the fungus at direct examination of the sample [3].
Hcc, responsible for “small cell” histoplasmosis or American histoplasmosis, is well-documented in the United States mainly in the valleys of Ohio and Mississippi, South America, and Asia. Hcd responsible for “large-form” histoplasmosis or African histoplasmosis is endemic in Central and West Africa and Madagascar [3, 5, 6]. We point out a third variety, H. capsulatum var. farcimimosum, involved in equine pathology that will not be detailed in this chapter.
Histoplasmosis can be challenging to diagnose because it is laborious and requires special characteristics for its revealing. According to the criteria recommended by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) and those of the Council of State and Territorial Epidemiologists (CSTE) [7, 8], an integrated approach including clinical, radiographic, and laboratory evidence is required. For laboratory diagnosis, several techniques are available as microbiology, histopathology, and immune-serological assays, depending on the clinical context and laboratory capabilities. Since 1978, the introduction of the Histoplasma antigen assay significantly improved the diagnosis by allowing a rapid, noninvasive, and sensitive method. Then, if culture remains the reference approach in most laboratories in endemic and non-endemic areas, non-culture methods are developing and much more improving [2, 9, 10, 11].
This review describes the current diagnostics for the laboratory identification of H. capsulatum, with focus on their performance and context-based value.
For Histoplasma capsulatum var. capsulatum, the inhalation of conidia from the environment (bat or bird guano) leads to Histoplasmosis syndrome or asymptomatic carriage in immunocompetent individuals. It can be self-limited especially in the lung or a progressive disseminated disease. Upon immunosuppression, the fungus can reactivate and be responsible for a localized or disseminated disease. Disseminated histoplasmosis has been classified as an AIDS-defining infection. There is a significant overlap of the pathophysiology and the clinical presentation as tuberculosis or cryptococcosis, sarcoidosis, and malignancy [1, 2, 3, 4, 6, 12].
The histoplasmosis syndromes can be evoked according the clinical presentation, the epidemiology, and the disabled. It can be expressed as [1, 2, 6]:
A pulmonary histoplasmosis presenting as acute, subacute, chronic, or pulmonary nodules.
A progressive disseminated histoplasmosis (PDH) that mainly concerns some particular populations (extreme age groups, immunosuppressed people including AIDS/HIV, iatrogenic origin). However, immunocompetent people defined as without obviously immunodeficiency can develop such syndrome when important inoculum.
A cerebral nervous system (CNS) histoplasmosis.
Other clinical findings as mediastinal histoplasmosis (adenitis, granuloma, mediastinitis).
For Histoplasma capsulatum var. duboisii, many features remain undiscovered as the reservoir niche, pathogenesis, and epidemiology because of the relatively low number of case reports. It expresses much more in skin and subcutaneous tissues than in lungs. Association as well with HIV is rare [5].
All types of clinical specimens can be processed according to symptomatology [1, 2, 4, 6, 7, 8]:
Bronchoalveolar lavage (BAL), sputum, and lung biopsy should be performed for patients with pulmonary symptoms
Bone marrow aspiration
Punctures of lymph node, pus, or exudates
Organ biopsies (lymph node, digestive tract, liver, skin, oral mucous)
Peripheral blood (EDTA or fungal blood culture vacutainers)
Cerebrospinal fluid (CSF)
Different microbiological approaches can be performed as on one hand mycological examination (direct, culture) and molecular assays (qPCR) and, on the other hand, histopathology. The performances depend on the specimens tested and are much more details on paragraph 5.4 (Table 1).
PHD | Acute pulmonary syndrom | Subacute pulmonary syndrom | Chronic pulmonary syndrom | Pulmonary nodules | Mediastinal histoplasmosis | CNS histoplasmosis | Other manifestations (pericarditis, rheumatological), | ||
---|---|---|---|---|---|---|---|---|---|
Culture | Pulmonary tissue or secretions (LBA, sputum) | x | x | x | x | (x): differential diagnosis | |||
Bone marrow | x | x (if associated PHD) | |||||||
Lymph nodes | x | (x) mediastinal | |||||||
Exudates | x | (x) Non viable yeasts | (x) Non viable yeasts | ||||||
Organ biopsy | (x) | x Non viable yeasts | |||||||
Peripheral blood | x | x (if associated PHD) | |||||||
Cerebrospinal fluid | x | ||||||||
histopathology | x | x Cytopathologic examination of BAL (50%) | x Non viable yeasts | (x) | |||||
Serology | (x) | x | x | X (low sensitivity) | x | X | x | ||
Antigen | x serum, urine +/-LBA to repeat | x (83%): serum, urine +/-LBA or if associated PDH | (x) up to 40% (urine) | (x) serum, urine +/-LBA | x |
Examination of liquid smears or fine-needle aspiration and/or tissue apposition on slides from all types of samples is carried out by staining with May-Grünwald-Giemsa (MGG). Using 10% KOH with or without calcofluoric acid, a chitin-binding fluorescent stain for the fungal cell wall, the yeasts can be easily visualized between slide and slip cover. For some specimens as the peripherical blood, cerebrospinal fluid, bronchoalveolar fluid, and cytocentrifugation may be required [3, 13, 14].
Diagnosis is possible according to the morphology of the yeasts.
Yeasts are spherical, small (2–5 μm in diameter), intensely violet colored, and surrounded by a clear halo. These yeasts are narrow-based budding yeast cells, usually intracellular (macrophage, histiocyte, etc.), and do not produce any filaments (Figure 1). The differential diagnosis includes Leishmania species, which is similar in size but has one kinetoplast [3, 6, 13, 14], Candida mainly glabrata and Cryptococcus yeast cell which is predominantly extracellular and strongly MGG stained.
Histoplasma capsulatum var. capsulatum on bone marrow smear, intramacrophagic yeast form, microscopic appearance, magnification ×1000 (photo by Emilie GUEMAS).
Yeasts cells are oval and large (8–15 μm by 4–6 μm), with a “hourglass” or “figure eight” budding form, a thick wall and a narrow budding. They may have inside fat droplets. These yeasts are intra- or extracellular, sometimes arranged in short chains of 2 or 3 [3, 6, 13, 14].
Specimens as pus from abscess, draining sinuses and bone marrow lesions, colic biopsy, or BAL smears are relatively contributive to the diagnosis [4, 6, 15] in disseminated histoplasmosis.
Direct examination is inexpensive, and according to the relatively typical appearance of the levuriform elements, it allows to quickly and easily provide presumptive evidence for histoplasmosis. However, doubts may remain, and then it requires trained personnel and further investigations. Indeed confusion can concern Hcc versus Cryptococcus sp., Candida glabrata, and Leishmania sp. and/or if the clinical picture is not very classical [3, 6, 13, 14] or Hcd versus Blastomyces dermatitidis, which looks like another yeast cell and differs with its broad base budding.
Histopathology consists in the research for elements evocative of the yeast form of H. capsulatum inside tissues. Different stains can be carried out such as Gomori Methenamine Silver (GMS), Giemsa, or periodic acid-Schiff (PAS) stains that are the most relevant for the diagnosis. Hematoxylin and eosin (H&E) staining is insensitive to detect the presence of H. capsulatum [3, 13, 14, 16].
This concept of juggling between different stains and the description of morphologies of the microorganism (shape, size variation, cell disposition) and the tissue (cell response) permit to distinguish other pathogens as Cryptococcus spp., Blastomyces dermatitis, Candida glabrata, Pneumocystis jirovecii, Coccidioides spp., Talaromyces (formerly Penicillium) marneffei, Leishmania spp., Toxoplasma gondii, and Trypanosoma cruzi. These differences are represented in Table 2.
Size (μm) | Cell disposition | Characteristic | Tissue response | Specific coloration | |
---|---|---|---|---|---|
Hcc | 2 - 5 | IC | Spherical with halo Narrow-based budding Grouped in clusters into macrophage | Granulamatous tissue response, necrosis | GMS, PAS |
Hcd | 6 - 12 | IC | Oval with halo | Granulamatous tissue response | GMS, PAS |
Cryptococcus | 3 - 8 | Facultative IC | Spherical with characteristic halo (thick capsule) Narrow-based budding | Predominantly granulomatous inflammation, necrosis, +/- fibrosis | Mucicarmin (capsulated yeast) Fontana-Masson (uncapsulated yeast) |
Blastomyces dermatitis | > 15 | EC | Round, Thick retractile wall Broad-based budding | Mixed suppurative and granulomatous inflammation | GMS, PAS, H&E |
Candida glabrata | 1 - 4 | EC | Oval to round No pseudohyphal production | Suppurative tissue response | GMS, PAS, H&E |
Coccidioides | 2 - 5 | IC/ EC | spherical Confusion when endospores are outside spherules or young spherules without endospores | Mixed suppurative and granulomatous inflammation, (Splendore-Hoëppli phenomenon likely) | GMS, H&E, +/-PAS |
Pneumocystis cysts | 5-8 | EC | Cysts | Minimal reaction | GMS, PAS, H&E |
Talaromyces marneffeï | 2-5 | EC | Small oval-shaped yeast Transverse septum No bud | Mixed suppurative and granulomatous inflammation | |
Leishmania | 2 - 5 | IC | Oval to round kinetoplast | MGG |
Diagnosis differential of H. capsulatum [2, 16, 13].
IC: intracellular, EC: extra cellular, GMS: Gromori Methenamine Silver, PAS: Periodique Acid Schiff:, GE, MGG: May-Grunwald Giemsa.
It usually shows a granulomatous reaction with “giant cells,” containing large rounded or oval-shaped elements (2–4 μm in diameter). Hcc is predominantly found phagocytosed within macrophages, histiocytes, and giant cells, often in clusters of many organisms, but sometimes they are in extracellular spaces.
The yeast phase of Hcc is very similar to other pathogens and not distinctive in tissues from several other endemic fungi. The misidentification occurs principally with Candida glabrata, Penicillium marneffei, Pneumocystis jiroveci, Toxoplasma gondii, Leishmania donovani, and Cryptococcus neoformans [9]. However, in the appropriate clinical context, the presence of H. capsulatum like yeast is able to confidently make a diagnosis of histoplasmosis and is indicative of active infection. Moreover, the immunohistochemistry reaction with H. capsulatum antibodies can be used to confirm diagnosis of histoplasmosis.
Hcc is large (6–12 μm) and the wall is thick and highly refractive, with a pseudo-capsulated appearance. The yeast is easily distinguishable from the other endemic fungi especially Blastomyces dermatitis [8].
Isolation of H. capsulatum remains the gold standard for the laboratory diagnosis of histoplasmosis. However, it requires both BioSafety Level 3 (BSL3) facilities to be manipulated [17] and usually invasive methods to obtain the specimens from which culture can be performed.
All specimen types can be used from superficial to deep ones.
Culture is performed on Sabouraud dextrose agar with antibiotics (chloramphenicol +/− gentamicin) +/− actidione that inhibits the contaminants. Other mediums can be used: brain heart infusion (BHI), yeast extract peptone agar (YEP agar) and potato dextrose agar (PDA) [3]. Mediums are incubated at 25–30°C for 6–8 weeks.
As the rate of growth is slow, the growth of the mycelial forms usually takes 2–3 weeks but may take up to 8 weeks. Colony is initially white and smooth and then becomes brown, with a granular or cottony texture. The reverse is white, yellow, or orange (Figure 2).
Culture of H. capsulatum on Sabouraud dextrose agar. Colony is white with a cottony texture (photo by Emilie GUEMAS).
Confirmation of the cultured organism as H. capsulatum requires complementary tests:
It allows determining microscopy morphology with identification characters [18]:
Hyphae: hyaline septated (2–3 μm in diameter),
Characteristic macroconidia: large, thick-walled, round, typically tuberculate, or knobby (7–15 μm in diameter).
Microconidia: smooth-walled spherical, pyriform (2–5 μm in diameter) on short branches or directly on the sides of the hyphae
The differential diagnosis includes Sepedonium sp. (Figure 3).
Histoplasma capsulatum, microscopic appearance with LPCB test, magnification ×400 (photo by Emilie GUEMAS).
The identification of the colony can be carried out by matrix-assisted laser desorption/ionization time off light (MALDI-TOF). Mass spectrometry by MALDI-TOF allows to confirm species accurately and quickly.
This identification technique is based upon the detection of highly abundant proteins in a mass range of 2–20 kDa by calculating their mass (m) to charge (z), m/z values. The spectrum thus obtained is compared with the reference spectra [19, 20].
This can be achieved using enriched media such as BHI or blood agar plates incubated at 35–37°C in a CO2-enriched atmosphere [3]. However, H. capsulatum does not convert easily depending on many parameters [13] as nutriments and temperature conditions, which can explain that this experiment is increasingly abandoned.
The urease test allows the distinction between Hcc and Hcd as it reveals the expression of urease strongly for Hcc and weakly for Hcd at 48 hours [3, 5].
Others tests performed from the cultured fungi such as DNA hybridization using a highly specific commercially kit (AccProbe; Gen-Probe, Inc., San Diego, CA®) or the detection of specific precipitin by the exoantigen test was used in some laboratories [10, 13]. They were gradually replaced by less time-consuming method as MALDI-TOF. They will not be more detailed in this chapter.
The lysis centrifugation method as Isolator® system followed by the inoculation of the collected buffy coat [11] into an appropriate media culture has been proved to be the most efficient for detecting Histoplasma in the blood in comparison with other methods such as conventional or automated methods such as Bactec MYCO/F Lytic bottle [21]. However, many laboratories preferred those alternative systems than the manual isolator system because they permit less pre-analytic processing and continuous automated monitoring of bottles for growth when automated [9].
The sensitivity of culture depends on the clinical manifestation, the clinical specimen, the state of immunity of the host, and the burden of disease [2, 9, 14]. Sensitivity is lower for patients with acute pulmonary histoplasmosis (40%) than for patients with disseminated histoplasmosis (75%) [2, 9, 10].
The diagnosis of disseminated histoplasmosis blood culture processed by lysis methodology and bone marrow shows higher sensitivity (60–90%). Conversely, respiratory samples presented poor sensitivity (0–60%) [2, 9, 10].
The limitations of the culture are the time frame for diagnosis, the mycological expertise required, and safety. Several weeks for growth of the fungus to establish the diagnosis are not consistent with the severity of the disease in immunosuppressed patients. Moreover, H. capsulatum poses an infectious risk and must be manipulated in a laboratory with BSL3.
Conversely, detection of H. capsulatum by automated methods such as the Bactec system has not shown optimal results with sensitivity of less than 50% [2, 9, 10, 11, 13, 14] in acute and disseminated histoplasmosis that need to be rapidly diagnosed for the prompt initiation of therapy.
Several protocols do exist based on Histoplasma-specific antibody detection with three routinely used assays: immunodiffusion test (ID), fixation complement test (FC), and indirect immunological assays (EIA) [9, 10, 11, 13, 14, 22, 23, 24, 25, 26]. Serology aims to confirm a previously contact with the pathogen, and it usually does not mean that the patient is making an acute infection. For histoplasmosis, in certain circumstances, serology can detect the acute phase of histoplasmosis. It is reported that the antibodies detection period is between 4 and 8 weeks but can be negative in immunodeficient patients [10, 14]. The serologic targets are the specific Histoplasma proteins M (a catalase) and H (a β-glucosidase) that are present in the entire yeast or an antigenic extract (histoplasmin or HMIN) used as deglycosylate or not, from mycelial culture. Another protein can be targeted, the protein C (a carbohydrate, galactomannan), that is less specific and can be responsible of cross-reactions with other fungi [9]. Their characteristics are summarized in the Table 3.
Complement fixation (FC) | Immunodiffusion (ID) | ELISA | Western Blott | |
---|---|---|---|---|
Mechanisms | A supplemented specific Ag induces Ag-Ab complexes | Precipitins Ac-Ag (H/M) on gel agar | Indirect sandwich ELISA | Visualisation of band profiles on nitrocellulose membranes |
Type of Ag | Entire yeast or HMIN | HMIN Prot M, Prot H | Yeast cell extract, ribosome, HMIN (glycosylayte/deglycosylate) | Histoplasma antigens of 115, 91,88, 83, 70 and 38 kDa from HMIN (glycosylayte/deglycosylate) |
delay | 3 -6 weeks | 4-6 weeks IgG anti-M → IgG M+H | 2 -4 weeks | 2-4 weeks |
Duration of positive antibodies after resolution | Months to years Months to years Persistent in recurrences | Prot M: up to 3 years | Months to years | Months to years |
Prot H: 1-2 years | ||||
Sensitivity | 72-95% | 70-95% | 75-100% | 45-100% |
Specificity | 70-80% | 100% | 91-100% | 94-100% |
Histoplasmosis meningitidis | When positive (culture usually negative (63%) | When positive (culture usually negative (44%) | Specificity: 93% Sensibility: 82% (26) | No data |
Acute infection | ++ | Band M (80%) Band H (7-20%) | 66-100% (9-10, 13) | 45-94% (13, 22) |
Chronic infection | + | Band M | 90% (9-10, 13) | 94-100% (13, 22) |
Special remarks | Interference with Rheumatoid factor and cold agglutinins | Positive after skin test Histoplasmine (M +++/H+) | Ribosome antigen and ptHMIN induces better response than glycosylate HMIN antigene. Best results with ELISA using ferrous metal | Better results when using ptHMIN Can detect early in the infection |
Kits/tests | House-made tests | House-made tests | House-made tests Commercialized tests with IgG, IgM, IgA | House-made tests |
Immunodiffusion assay qualitatively detects the precipitating antibodies to antigens M and H on agar gel. The H band appears after the M band, and the presence of both bands is highly significant for histoplasmosis diagnosis. Thus, M band is detectable in most patients with acute infection and persists for long periods of time up to 3 years after disease resolution and is often present in chronic forms [9, 10, 14]. It does not distinct between active from latent or resolved infection. H band is less frequent, confirms acute infection only in 7% according [13], remains present 1–2 years after disease resolution, and indicates a more severe form of the disease. This method is simple, reliable, and inexpensive.
Complement fixation method quantitatively measures the presence of complex antigen antibodies in a patient’s serum against the entire yeast form or mycelial antigen (HMIN) from 3 to 6 weeks following infection [13]. Interlaboratory results vary as it is entirely strain-dependent for the antigen preparation. It is quite more sensitive bus less specific than the ID. Indeed, it presents numerous cross-reactions with other fungi and interference with rheumatoid factor and cold agglutinins [13]. A threshold defined as up to 1:32 or titer a 4-fold rise indicates an active infection.
This method does not allow differentiation between an active infection and an old infection. Indeed, antibodies require 4–8 weeks to become detectable in peripheral blood. Serology is unreliable in patients with a reduced ability to produce antibodies, and then it is often negative in immunocompromised patients [13, 14]. Antibody testing is most useful for subacute and chronic forms of histoplasmosis [2].
Western blot immunoassay uses Ag proteins of different kDa that will complex with the specific Histoplasma antibodies on a nitrocellulose band. It showed good results but does not exist as a commercial kit, so it can be fastidious to set up. The sensibility is improved by the treatment of the Ag (Histoplasmin) [22].
Interferon gamma release assay (IGRA): this test is based on the quantification of lymphocyts-released interferon (IFN) -γ after restimulation in vitro of the cell-mediated immunity with the same specific antigens. Recently, Rubio-Carrasquilla et al. [23] considered it as a promising screening method to detect individuals with latent Hc infection, even decades after the primary infection.
Latex agglutination tests were developed as a commercial kit, but false positives results were found in patients with tuberculosis. It was compared as more sensitive than CF [13].
A hemagglutination test was available but failed to differentiate B. dermatitidis [13].
A recent meta-analysis [9] interested in the global sensitivity of antibody detection for disseminated histoplasmosis and showed a low sensitivity of 58% in contrast with high specificity (100%). But there is a real distinction between the different assays. WB and ELISA methods have the highest analytical performance, with sensitivity of up to 90% when used in ptHMIN. This can explain that it is relevant to associate different methods in order to improve the diagnosis.
Cross-reactivity with granulomatous disease, tuberculosis, and sarcoidosis can occur with immunodiffusion and complement fixation tests. Moreover, serologic cross-reaction can occur with other common fungal pathogens like Blastomyces dermatitidis, Coccidioides immitis, Aspergillus fumigatus, and Paracoccidioides brasiliensis [24, 25].
The presence of antibodies in the CSF allows making the diagnosis of Histoplasma meningitis [2, 26].
Circulating specific-Histoplasma polysaccharide antigen (HPA) detection is a useful option for diagnosis [9, 13, 14, 27, 28]. Histoplasma galactomannan is the target of the antigenic detection. Since its introduction in 1986 [13, 14], as a solid-phase radioimmunoassay, it was developed into a sandwich enzyme immunoassay (EIA) [2, 13, 27, 28, 29] with different improved generations and recently into a lateral flow assay (LFA) [30]. Their performance is related to the choice of the antibodies used monoclonal versus polyclonal, and the conjugate (Biotine or horseradish peroxidase) [13].
This polysaccharide mostly found in the cell wall of Aspergillus sp. is commonly used for invasive aspergillosis diagnosis in high-risk immunosuppressed patients suffering of solid organ transplantation or hematological malignancies. Cross-reactivity with the histoplasma antigen detection is reported suggesting that this test could be a potentially helpful diagnostic test for histoplasmosis in HIV-infected patient because of the low incidence of invasive aspergillosis in this population. The sensibility of this test for diagnosis of disseminated histoplasmosis in AIDS patients is 77% and specificity is 100% [31].
This noninvasive method can be performed in urine, serum, and other body fluids as LBA [2, 9, 10, 13, 14] and is the simplest diagnostic method, easily implemented in low- and middle-income countries.
It allows a rapid diagnosis especially for immunosuppressed patients with severe acute or disseminated histoplasmosis. It is less sensitive than serology for the diagnosis of subacute and chronic pulmonary histoplasmosis [2, 9].
Antigen detection in urine is more sensitive than in serum for the diagnosis of disseminated histoplasmosis (95% versus 86% for HIV-infected patient) [9, 10, 11]. However, antigen detection in urine is less useful for pulmonary forms or chronic histoplasmosis.
This method has also been applied to other body fluids, including BAL for patient with pulmonary symptomatology and CSF for Histoplasma meningitis. Antigen was detected in the CSF of 66% of immunosuppressed-infected patient patients who had Histoplasma meningitis [26].
If useful for the diagnosis, it can also monitor the antigen clearance, particularly in serum and thus appears as an useful marker for treatment response [32].
Moreover, it has proven its applicability to infected animals that may act as potential reservoirs for humans [28, 29].
Cross-reactivity of antigen testing occurs in patients who have other fungal infections, including infections by Blastomyces dermatitidis, Paracoccidioides brasiliensis, and Penicillium marneffei [33]. The most problematic issue is differentiating histoplasmosis and blastomycosis because the geographic areas overlap.
Recently, a lateral flow assay (LFA) has been developed and evaluated for rapid diagnosis of histoplasmosis. This point of care antigen detection in serum allows rapid results with high analytical performance. It is based on the using of rabbit polyclonal antibody that recognizes galactomannan antigen of H. capsulatum. Indeed, sensitivity is under 95% and specificity is 90%. Cross-reactivity occurs principally with paracoccidioidomycosis [30].
Molecular methods can improve and accelerate the histoplasmosis diagnosis with a high analytical sensibility and specificity [9, 10, 34, 35, 36]. This combined with turnaround times shorter than those of other diagnostics. It is much more safety and reduces the risk of laboratory acquired histoplasmosis when handle its positive culture. Several applications can be linked to the use of PCR based techniques as (i) human diagnosis from different samples, with an increasingly use for the imported cases diagnosis in non-endemic areas [9, 10, 11, 13], (ii) environmental exploration for revealing the histoplasmosis reservoir [35], (iii) and prevention policies and strategies for exposure risk [2].
There are no currently official approved molecular assays for H. capsulatum that are directly applicable to clinical specimens and no commercially kits are available [9, 10, 34]. However, there are numerous reports of the laboratory-developed PCR assays (in house PCR) using the different type of PCR (conventional, nested and quantitative) and a variety of molecular targets. The most relevant are the Internal Transcribed Spacer (ITS) multicopy region of the ribosomal DNA, genes encoding the M antigen or the 100-kDa-like protein [9, 34]. Most studies in the literature evaluated the performance of nested PCR in the diagnosis of PDH, this assay is associated with the increased risk of amplicon contamination, because of the manipulation of amplified products.
A multiplex approach can also be performed. For example, in a reference laboratory in Spain they developed a multiplex qPCR for H. capsulatum, Pneumocystis jirovecii and Cryptococcus neoformans [11].
As a full tool to Histoplasmosis diagnosis, molecular assays can be performed on different types of specimens including respiratory secretions, biopsies, bone marrow, blood, or sera.
For diagnosis of disseminated histoplasmosis (PDH), sensitivity and specificity are 95% and 99%, respectively [2, 9]. Sample of blood and bone marrow have an excellent sensitivity (100%) in immunocompromised patients with disseminated histoplasmosis, whereas it is weaker in immunocompetent patients [2, 11].
Moreover, sensitivity increases by testing more than one sample per patient in cases with extra-pulmonary histoplasmosis. So, in case of high suspicion, clinicians should repeat and diversify samples [2, 9, 11, 34].
Recent findings in molecular biology permit to evaluate genetic diversity using multilocus sequence typing (MLST) OR RAPD-PCR [36]. This could be Interesting to associate genotypes and clinical presentation.
Loop-mediated isothermal amplification (LAMP) is a highly efficient, sensitive, specific and cost-effective isothermal amplification method that uses at least four primers, recognizing six different regions in the target sequence (Figure 4) and results in a self-primed DNA [37].
Principe of LAMP [38].
In LAMP, the target sequence is amplified at a constant temperature of 60–65°C using either two or three sets of primers and a polymerase with high strand displacement activity in addition to a replication activity. The amount of DNA produced in LAMP is considerably higher than PCR-based amplification.
To increase the reaction sensitivity, the ITS region was used as target, since it is a multicopy sequence and also because it is considered an important barcoding sequence for fungal identification, being conserved among H. capsulatum strains and divergent from other fungi, ensuring high specificity.
Forward inner primer (FIP) and backward inner primer (BIP) have inverted sequences attached at the 5′ end, named F1c and B1c, which are complementary to an internal sequence from the amplified strand, forming a loop at each extremity of a single strand DNA.
The outer primers (F3 and B3) anneal upstream to the FIP and BIP, acting as a binding site for DNA polymerase, which, in the LAMP reaction, also contains the strand displacement activity.
LAMP results can be observed using several strategies with minimal ambiguity with real-time turbidimetry (magnesium pyrophosphate formation), fluorescent compounds (Sybr Green, Eva Green, SYTO, calcein), magnesium colorimetric titration, fluorescent-labeled probes, quencher-labeled primers, dye-labeled primers, and PH-sensitive dyes.
LAMP can be used on samples of whole blood or bone marrow for patients suspected of progressive disseminated histoplasmosis (PDH).
A new assay, the so-called ITS LAMP, showed no cross-reactivity when assayed with DNA from other pathogenic or environmental fungi. The assay is able to detect isolates from all geographical clades of H. capsulatum, including Hcd. In comparison with Hcp100 nPCR, it reached sensitivity of 83% and specificity of 92% [35].
This method remains cost-effective with or without the extraction DNA step and did not require a thermocycler or an electrophoresis apparatus. It saves time with test performed in less than 200 minutes [35]. However, this little-known and recent method is currently underused and much more reserved for resource-limited laboratories. It should evolve in the next years to come and need further evaluation to be routinely used.
The performance for each test according the clinical context is summarized in Table 4. It considers global sensitivity without any distinction between the different protocols (antigen preparation, methods, ...).
PHD | Acute pulmonary syndrom | Subacute pulmonary syndrom | Chronic pulmonary syndrom | Mediastinal histoplasmosis | CNS histoplasmosis | |||
---|---|---|---|---|---|---|---|---|
(2) | (9) | |||||||
Ag detection | 92 | 95 | 83 | 30 | 88 | 5 | 66 | |
81 | 31 | |||||||
Serology | 75 | 58 | 64 | 95 | 83 | 83 | 59 | |
63 | 54 | |||||||
Pathology | 76 | NE | 20 | 42 | 75 | 75 | ||
culture | 74 | 77 | 42 | 54 | 67 | 67 | 38 | |
40 | 33 | |||||||
Molecular Biology | 95 |
The different performances (sensibilité %)of the methods are summarized in this table adapted to azar et al. (2), Caceres et.al (9) and Wheat et.al (26).
PDH: Progressive histoplasmosis disseminated, CNS: Central nervous system, NE: Non evaluated.
It highlights that Ag detection is the best diagnosis tool for PHD and SCN histoplasmosis, serology for the subacute/chronic form, and the culture although this is the reference method remains less sensitive.
Histoplasmosis remains a severe and neglected disease for which early diagnosis of invasive fungal infections is critical to allow a prompt patient care. Indeed the mortality rate among HIV/AIDS patients diagnosed with histoplasmosis is high: 42% mortality for disseminated histoplasmosis if treatment is delayed and 100% if antifungal therapy is not prescribed.
The gold standard for histoplasma diagnosis remains culture. It’s a time-consuming process and has limitations in sensitivity. Moreover, it requires invasive procedure and mycological expertise.
Nonculture methods have been developed to improve and accelerate diagnosis of histoplasmosis, such as histoplasma antigen detection, antibody detection, and molecular biology. It should have conjunction between the different tools of diagnosis to be reliable in the histoplasmosis management regarding the wide range of clinical features.
Tropheryma whipplei, formerly Tropheryma whipplei, is an intracellular gram-positive Actinobacteria ubiquitous in the environment that is involved in a large variety of clinical forms [1, 2]. The initial name was proposed by Relman et al. in 1992, and comes from the Greek trophe, nourishment, and eryma, barrier, due to the malabsorption it causes, and from the surname of George Hoyt Whipple [3]. In 2001, the name of the bacterium was slightly modified to conform to the proper spelling of Dr. George H. Whipple’s name [4].
Dr. Whipple was the first who reported, in 1907, a “hitherto undescribed disease” he named “intestinal lipodystrophy” in a 36-year-old man with malabsortion, weight loss, diarrhea, migratory polyarthritis, cough and mesenteric lymphadenopathy [5]. Now, we refer to this disease as Whipple’s disease. Although this disease was first described at the beginning of the last century, the hypothesis of its bacterial origin goes back to the late 40’s and was supported with use of periodic acid-Schiff (PAS) staining and the success of the first antibiotic treatment [6, 7]. Subsequently, the presence of the microorganism was confirmed by electron microscopy (rod-shaped organism), polymerase chain reaction (PCR) of the 16S rRNA and finally by culture [1, 3, 8, 9, 10, 11, 12]. The isolation and later sequencing of its genome made possible to define its antibiotic susceptibility [13, 14, 15, 16].
Until recently, T. whipplei was known to be only the causative agent of Whipple’s disease, now called by some authors “classical Whipple disease”, a rare chronic multisystemic infection [5]. Incidence of Whipple’s disease was reported in approximately 1 per 1.000.000, although it remains unclear and epidemiological estimates varies among different studies [17, 18, 19]. Classical form of Whipple’s disease usually involves the gastrointestinal tract, joints and central nervous system with malabsorption, diarrhea, abdominal pain and/or weight loss and arthralgia as prominent manifestations. Cardiac, ocular or other organs involvement has been also reported in patients with Whipple’s disease [20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. The knowledge of the genome of T. whipplei has allowed developing specific and sensible tools that have let to involve this microorganism in a broad spectrum of clinical conditions [13, 14]. Therefore, T. whipplei can produce acute localized forms of infection such as pneumonia [30, 31], bacteremia [32], acute diarrhea [33, 34], uveitis [35, 36]; sub-acute forms such as adenitis [37] and chronic forms as uveitis [38], and, overall, endocarditis [39, 40].
T. whipplei has also been detected in asymptomatic carriers based, mainly, on stools and saliva analysis with very different prevalence among populations [41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]. The carriage of T. whipplei varies considerably across studies and subjects. Many factors are involved in those differences such as the geographical region, exposure or the age of the studied subjects. The prevalence of asymptomatic carriers of T. whipplei in Africa and Asia is higher than in Europe and it is also higher in children than in adults [49, 50, 51, 53]. Actinobacteria are environmental microorganisms that can be found in freshwater, soil or seawater sediments, this fact could explain the high prevalence of T. whipplei in people expose to sewage and sewage plant workers [2, 41, 47, 54, 55]. People in contact with patients with Whipple’s disease, as patients’ relatives or carriers, or those with poor hygiene conditions such as homeless, also presents higher prevalences [56, 57, 58, 59]. Differences between the targets used for the PCR and the samples used have been also observed and could explain these reported differences [52, 60]. Li et al. assessed that genomic variants of T. whipplei are associated with neither the organotropism of the bacteria nor the geographical residence of the individuals [61], however later studies show that different genotypes are more frequent in some populations [34, 56, 58, 62]. Therefore, despite Whipple’s disease is rare, the high number of healthy carriers, the ubiquitous presence of the bacteria in the environment [41, 47, 57, 59] and the possibility of interhuman transmission [49, 56, 57, 58, 59, 63, 64] make T. whipplei a common bacterium in humans.
First implication of T. whipplei as causative agent of infective endocarditis was reported in Switzerland in 1997, in a patient with blood culture negative endocarditis (BCNE) using a broad-range PCR followed by sequencing [64]. Curiously, first stable cultivation of the bacterium of Whipple’s disease was carried out in 2000, from the mitral valve of a patient with BCNE [1]. Since then, the number of cases has increased and to date T. whipplei endocarditis is one of the more frequent causes of BCNE in some areas [65, 66].
BCNE is a relative frequent condition among endocarditis representing 5–30% in big series [67, 68, 69, 70]. The main reasons are the previous administration of antimicrobials and fastidiously culture microorganisms [67, 68, 71, 72, 73, 74, 75]. The application of molecular tools has allowed doing new approximations to the etiology of BCNE and new agents have been involved [69].
Sporadic cases of T. whipplei endocarditis have been reported from different countries, but there are few published series of T. whipplei endocarditis. France, Spain, Germany and Switzerland have the largest number of diagnosed cases [39, 64, 65, 70]. This fact could be due to their larger experience in the knowledge and use of the molecular tools to heart valves [40]. The incidence of T. whipplei endocarditis among BCNE varies depending on the series. The incidence rate estimated varies between 2.6% and 7.1% depending on the country (France: 2.6% [76], Spain and Denmark: 3.5% [70, 77], Switzerland: 4.3% [78], Germany: 6.3% [65], Czech Republic: 7.1% [79]). However, it is difficult to know the true incidence of T. whipplei endocarditis since its study by molecular tools is not the rule in all hospitals. Thus, several parameters seem to affect the incidence of T. whipplei endocarditis such as the diagnostic tools available, the working group experience and the true incidence itself [39].
A total of 174 cases of T. whipplei endocarditis have been reported between 1999 and 2020 [21, 39, 65, 70, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117]. The vast majority of cases were men (>85% of the cases) and the average age was around 57 years (range: 33–81 years).
Comorbidities or other predisposing risk factors have been not uniformly reported in the literature [118]. Previous valvular affectation has been documented in 21% of the diagnosed cases, while prosthetic valve replacement previously to the event seems not an important condition (<5% of the available series). Alcohol abuse has been reported in very few cases, however alcohol intake (>60 g/d) was referred by the 23.5% of the patients in the Spanish series [70]. Previous cardiac condition or a cardiac event (i.e., coronary heart disease) has been observed in 50% of cases [66]. Data of historical immunosuppression forms (autoimmune disease or immunosuppressive therapies such as steroids or tumor necrosis factor inhibitors) have been reported in 21 cases (12%).
Classical Whipple’s disease has been reported as concomitant with the diagnose of endocarditis in few cases (6%) [66, 70]. However, in lot of cases this data is not available and in some of them although, classical Whipple’s Disease has not been diagnosed, it cannot be excluded.
The signs and symptoms T. whipplei endocarditis are not the typical ones. Fever has been only reported in 21% of the cases. Cardiac failure and arthralgia have been shown as the main presenting symptoms and have been described in 43% and 52% of patients, respectively. Cardiac failure is of special interest because it is the first manifestation in a high percentage of patients. Long lasting arthralgias presence as a prominent symptom varies depending on the series. While in the French series arthralgias were present in 75% of patients [39], in the Spanish one this condition was present in 53% [70]. These variations could be due to this symptom is sometimes weak and only detected after an exhaustive clinical research. Some authors suggest that, in those patients with sub-acute endocarditis and low-grade fever or not fever, if arthralgias are present, T. whipplei as causative agent should be suspected [39, 103]. Asthenia and malaise lasting more than six months were notified by the 41.2% of the patients in one series [70]. Other signs such as weight loss or gastrointestinal symptoms have been observed in 25% and 21% of the reported patients [118]. In addition, central nervous system manifestations (i.e., emboli) have been detected in 16% of patients.
The valve involved in patients with T. whipplei endocarditis has been predominantly the aortic (63%). Involvement of multiple valves (mainly aortic valve in combination with the mitral or tricuspid valve, and mitral-tricuspid affection) has been noticed in 23% of patients. Only mitral valve affectation has been observed in 20% of patients and tricuspid valve just in six of 174 patients (3%). Native valve was affected in the vast majority of cases.
Echocardiography features are one of the most valuable tools for suspecting infectious endocarditis. According to the literature, when these data were recorded, presence of vegetations was observed in more than the half of patients [66]. In our series, echocardiography was performed in all patients (both transthoracic and transesophageal in more than 80%) and allowed the diagnosis of infectious endocarditis in 70% of patients through the visualization of vegetations in the vast majority, or by indirect signs in a few [70]. Valve vegetation from a patient after cardiac valve surgery is shown in Figure 1. In the French series, echocardiography showed vegetations in 78% of the patients, but these data are not recorded in the German one [39, 65]. Data of vegetation appearance or size is rarely reported. Data of size vegetations when available, shown a minimum size of 5 mm and a maximum of 33 mm [118].
Valve vegetation specimen obtained after surgery from a patient with T whipplei endocarditis.
The main laboratory recording abnormalities at the time of the diagnosis have been anemia, which was detected in 40% of patients but this date can reach 88.2% in some series, and increasing of C-reactive protein in range from 2.3 to 137 mg/L [70]. In patients who had heart failure, B-type natriuretic peptide (BNPs) of up to 2536 ng/L has been also reported [118].
Main characteristics of patients are shown in Table 1.
% (No.) | ||
---|---|---|
Patients (No.) | 174 | |
Epidemiological data | ||
Medium Age (years) | 57 | |
Male gender | 85% (148) | |
Medical history | ||
Immunosuppression | 12% (21) | |
Valvular abnormality | 21.8% (38) | |
Affected valve | ||
Aortic | 63% (110) | |
Mitral | 20.7% (36) | |
Tricuspid | 3.4% (6) | |
Multiple valves | 22.9% (40) | |
Presenting symptoms | ||
Arthralgia | 51.7% (90) | |
Heart failure | 43% (75) | |
Weight loss | 25.2% (44) | |
Fever | 21.3% (37) | |
Central nervous system | 16.1% (28) | |
Gastrointestinal symptoms | 20,7% (36) | |
Laboratory abnormalities | ||
Anemia | 39,1% (68) | |
Outcome | ||
Valve surgery | 73.5% (128) | |
Death | 17.8% (31) |
Main clinical epidemiological, clinical and outcome characteristics of patients with T. whipplei endocarditis reported in the literature. Updated from McGee et al. [118].
The suspicion and diagnosis of T. whipplei endocarditis is complicated. To date, 174 cases have been reported but, due to the difficulties for the identification of T. whipplei, the prevalence of the endocarditis it causes could be underestimated [119].
Diagnosis of T. whipplei endocarditis remains a challenge for several reasons. One of them is because this endocarditis does not exhibit the typical sings (no fever nor peripheral stigmata and low inflammatory response) and blood cultures used to be negative; therefore, modified Duke’s criteria are ineffective for diagnosis before heart valve analysis [39]. In this sense, some series have shown that only 3.6% patients met criteria for endocarditis according to the modified Duke criteria and 60.7% met for possible endocarditis [39]. It is very difficult to perform a microbiological or histological diagnose without analyzing the surgical remove valve. Routine blood and tissue culture are not often useful for the diagnosis. Thus, the diagnosis is often made post-surgery and valve analysis requires specialized laboratories, moreover if culture of the bacteria is intended to carry out.
Different targets have been used for molecular analyses. PCR based on the 16S rRNA amplification and subsequent sequencing has been widely used and has been the first-line screening in our series. However, some authors alert that this broad-spectrum PCR could have a limited sensitivity (value sensitivity 60%, specificity 100%) [120], while specific qPCR for T. whipplei have showed higher sensitivities [48, 60]. So, if 16S rRNA PCR has been negative, specific targets should be used in highly suspected cases of T. whipplei. At least 2 of the PCRs must be positive and their sequences have to show higher identity with the bacterium studied. PCR yield in other specimen different from valves varies depending on the specimen type and should be interpreted with caution according to the clinical context [66, 118]. A positive PCR result from a non-sterile site such as stool or saliva samples has been used to diagnose classical Whipple’s disease and to detect asymptomatic carriers, but is nor sensible nor specific for the diagnosis of T. whipplei endocarditis without clinical evidence of disease [42, 121, 122].
The role of serological tests in the diagnosis of Whipple’s disease is unclear because healthy carrier patients may paradoxically have a higher immune response to T. whipplei compared with patients with active Whipple’s disease [123]. Specific tools for an indirect diagnose for T. whipplei endocarditis are not available. This fact does not occur in other BCNE such as Q fever endocarditis or Bartonella spp. endocarditis. Curiously, a patient with Q fever and T. whipplei concomitant endocarditis has been described [124]. Valvular inflammatory infiltrates of T. whipplei–infected heart valves mainly consisted of foamy macrophages and lymphocytes. These macrophages have been observed in valvular tissue and in the vegetations on the surface of the heart valves. The dense and granular material that foamy histiocytes are filled with is strongly positive on PAS staining or immunopositive with a specific antibody against T. whipplei [39]. Thus, PAS staining and specific immunohistochemistry test (IHC) using specific antibodies against T. whipplei of cardiac valves could be useful for the diagnosis of T. whipplei endocarditis (Figure 2).
PAS staining positive in valvular tissue and vegetation.
According to the literature, 156 patients have been diagnosed of definite T. whipplei endocarditis by direct examination of the valve, of which more than 70% had positive PCR, almost 40% reported PAS staining positive on valve tissue and around 50% showed positive IHC. Seven patients were diagnosed of possible endocarditis regarding to vegetations on valve imaging and classical Whipple’s disease concomitant diagnosis. In these last cases, 85% had positive PCR on different specimen such as duodenal sample, stool, saliva or central nervous system samples and more than 50% had positive PAS staining in other tissue specimen [118].
In summary, definitive T. whipplei endocarditis could considered if positive results of PAS staining and/or specific IHC test using specific antibodies against T. whipplei and/or 2 positive results of PCR assays targeting 2 different sequences in a cardiac valve specimen are met [60]. It is important to notice that in patients with subacute endocarditis with negative blood cultures and low-grade fever (or not fever), if arthralgias are present, T. whipplei as causative agent should be suspected [39, 103].
The optimal treatment of IE caused by T. whipplei remains uncertain. Treatment options and duration are based on previous experience and expert opinion owing to the microorganism’s nature, the lack of large series (because of the low incidence) in which follow-up is documented and because clinical trials have not been developed [74]. Recommendations are mainly based on the experience obtained from the treatment of classical Whipple’s disease and other types of BCNE such as Q fever endocarditis [125, 126]. Two weeks treatment with ceftriaxone, followed by 1 year of trimethoprim/sulfamethoxazole, has been the most recommended treatment for years [126]. However, in vitro studies have shown best results with the combination of doxycycline and hydroxychloroquine [127, 128].
According to the literature, treatments used in T. whipplei endocarditis include, in most cases, two weeks of parenteral high dose of ceftriaxone (others such as meropenem, penicillin G have been also used) followed by an oral treatment strategy of 12 months with sulfamethoxazole (160/800 mg BID) or, at least, 18 months of doxycycline (100 mg BID) plus hydroxychloroquine (600 mg/d), in a smaller proportion [125, 129, 130]. Available data indicate that the average treatment length (range) has been 17 months (12 months to indefinite) [118].
Last European guidelines published in 2015, recommend doxycycline (200 mg/24 h) plus hydroxychloroquine (200–600 mg/24 h) orally for at least 18 months (in the case of central nervous system involvement, sulfadiazine 1.5 g/6 h orally must be added to doxycycline). As alternative therapy, 2–4 weeks of ceftriaxone (2 g/24 h intravenously) or 2–4 weeks of penicillin G (2 million U/4 h) and streptomycin (1 g/24 h) intravenously can be used, followed by, at least, 1 year of oral trimethoprim/sulfamethoxazole (800 mg/12 h) [74]. It is likely that this recommendation was included after taking into consideration an in vitro T. whipplei resistant to trimethoprim, a case report of a patient with clinically acquired resistance to trimethoprim/sulfamethoxazole and the cases of T. whipplei endocarditis relapses after treatment with trimethoprim/sulfamethoxazole which were apparently cured after two years of doxycycline and hidroxychloroquine [109, 114, 131, 132]. Furthermore, some authors do not recommend the use of trimethoprim/sulfamethoxazole because the clinical, microbiological and genetic data analyses show that it is an antibiotic not efficient for the management of T. whipplei endocarditis [109]. In fact, three T. whipplei endocarditis relapses after treatment with trimethoprim/sulfamethoxazole have been published.
After the end of treatment, some authors recommend checking for the presence of T. whipplei in blood, saliva, and fecal samples every six months for two years and every year for the entire life of the patient [39]. If colonization is detected, they recommend treating again, but there is not still evidence for this procedure.
Follow-up data and long-term outcome of the treatments used in this condition have not been widely reported. These data are well documented in the Spanish series. Although in this series only the 35% of the patients received treatment according to guidelines, all the treatment lines used in this cohort in the management of T. whipplei endocarditis were effective and well tolerated and therapeutic failures or relapses were not detected either during the treatment or after it was finished [133]. Furthermore, no major complications were detected once the treatment was established or during the follow-up. Even though, follow-up of all patients continues in order to identify possible late relapses. It has been demonstrated that doxycycline plus hydroxychloroquine treatment of duration shorter than 18 months was not associated with either relapses or fatal outcomes. Moreover, data suggest that, with a very careful post-treatment monitoring, in patients who require the replacement of the infected valve and without classical manifestation of Whipple’s disease, replacement of the affected valve and a shorter duration antimicrobial treatment might be sufficient [133].
Since T. whipplei is not present in the stool or saliva of patients with endocarditis caused by this microorganism and in the absence of other biological markers indicating the discontinuation of the antimicrobials, other tools are needed. In this regard, the role of PCR of urine should be explored both as a tool for monitoring patients post-treatment and the non-invasive diagnosis of T. whipplei endocarditis [134].
In the last years and with the development of molecular tools, new cases of T. whipplei endocarditis have been diagnosed. For this reason, although T. whipplei infective endocarditis is an infrequent condition has emerged as an important differential diagnosis for BCNE. Endocarditis due to T. whipplei is often slowly progressive, similar to that caused by Coxiella burnetii and Bartonella spp. and it could be diagnosed with specific procedures when BCNE undergo cardiac surgery. An early and appropriate diagnosis is required since this condition has a very good course and prognosis when the appropriate treatment is started (including surgery). In our opinion, patients with unexplained valve destruction which requires cardiac surgery, an exhaustive clinical investigation must be performed and removed valves should be studied by molecular tools for to rule out an underlying infectious endocarditis.
The authors declare no conflict of interest.
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\\n\\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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The Corresponding Author (acting on behalf of all Authors) and INTECHOPEN LIMITED, incorporated and registered in England and Wales with company number 11086078 and a registered office at 5 Princes Gate Court, London, United Kingdom, SW7 2QJ conclude the following Agreement regarding the publication of a Book Chapter:
\n\n1. DEFINITIONS
\n\nCorresponding Author: The Author of the Chapter who serves as a Signatory to this Agreement. The Corresponding Author acts on behalf of any other Co-Author.
\n\nCo-Author: All other Authors of the Chapter besides the Corresponding Author.
\n\nIntechOpen: IntechOpen Ltd., the Publisher of the Book.
\n\nBook: The publication as a collection of chapters compiled by IntechOpen including the Chapter. Chapter: The original literary work created by Corresponding Author and any Co-Author that is the subject of this Agreement.
\n\n2. CORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\n2.1 Subject to the following Article, the Corresponding Author grants and shall ensure that each Co-Author grants, to IntechOpen, during the full term of copyright and any extensions or renewals of that term the following:
\n\nThe aforementioned licenses shall survive the expiry or termination of this Agreement for any reason.
\n\n2.2 The Corresponding Author (on their own behalf and on behalf of any Co-Author) reserves the following rights to the Chapter but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Chapter as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Corresponding Author confirms that they (and any Co-Author) are and will remain a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Chapter and all versions of it created during IntechOpen's editing process (including the published version) is retained by the Corresponding Author and any Co-Author.
\n\nSubject to the license granted above, the Corresponding Author and any Co-Author retains patent, trademark and other intellectual property rights to the Chapter.
\n\n2.3 All rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the Corresponding Author's or any Co-Author’s specific approval.
\n\n2.4 The Corresponding Author (on their own behalf and on behalf of each Co-Author) will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Chapter as a consequence of IntechOpen's changes to the Chapter arising from translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits.
\n\n3. CORRESPONDING AUTHOR'S DUTIES
\n\n3.1 When distributing or re-publishing the Chapter, the Corresponding Author agrees to credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen. The Corresponding Author warrants that each Co-Author will also credit the Book in which the Chapter has been published as the source of first publication, as well as IntechOpen, when they are distributing or re-publishing the Chapter.
\n\n3.2 When submitting the Chapter, the Corresponding Author agrees to:
\n\nThe Corresponding Author will be held responsible for the payment of the Open Access Publishing Fees.
\n\nAll payments shall be due 30 days from the date of the issued invoice. The Corresponding Author or the payer on the Corresponding Author's and Co-Authors' behalf will bear all banking and similar charges incurred.
\n\n3.3 The Corresponding Author shall obtain in writing all consents necessary for the reproduction of any material in which a third-party right exists, including quotations, photographs and illustrations, in all editions of the Chapter worldwide for the full term of the above licenses, and shall provide to IntechOpen upon request the original copies of such consents for inspection (at IntechOpen's option) or photocopies of such consents.
\n\nThe Corresponding Author shall obtain written informed consent for publication from people who might recognize themselves or be identified by others (e.g. from case reports or photographs).
\n\n3.4 The Corresponding Author and any Co-Author shall respect confidentiality rights during and after the termination of this Agreement. The information contained in all correspondence and documents as part of the publishing activity between IntechOpen and the Corresponding Author and any Co-Author are confidential and are intended only for the recipient. The contents may not be disclosed publicly and are not intended for unauthorized use or distribution. Any use, disclosure, copying, or distribution is prohibited and may be unlawful.
\n\n4. CORRESPONDING AUTHOR'S WARRANTY
\n\n4.1 The Corresponding Author represents and warrants that the Chapter does not and will not breach any applicable law or the rights of any third party and, specifically, that the Chapter contains no matter that is defamatory or that infringes any literary or proprietary rights, intellectual property rights, or any rights of privacy. The Corresponding Author warrants and represents that: (i) the Chapter is the original work of themselves and any Co-Author and is not copied wholly or substantially from any other work or material or any other source; (ii) the Chapter has not been formally published in any other peer-reviewed journal or in a book or edited collection, and is not under consideration for any such publication; (iii) they themselves and any Co-Author are qualifying persons under section 154 of the Copyright, Designs and Patents Act 1988; (iv) they themselves and any Co-Author have not assigned and will not during the term of this Publication Agreement purport to assign any of the rights granted to IntechOpen under this Publication Agreement; and (v) the rights granted by this Publication Agreement are free from any security interest, option, mortgage, charge or lien.
\n\nThe Corresponding Author also warrants and represents that: (i) they have the full power to enter into this Publication Agreement on their own behalf and on behalf of each Co-Author; and (ii) they have the necessary rights and/or title in and to the Chapter to grant IntechOpen, on behalf of themselves and any Co-Author, the rights and licenses expressed to be granted in this Publication Agreement. If the Chapter was prepared jointly by the Corresponding Author and any Co-Author, the Corresponding Author warrants and represents that: (i) each Co-Author agrees to the submission, license and publication of the Chapter on the terms of this Publication Agreement; and (ii) they have the authority to enter into this Publication Agreement on behalf of and bind each Co-Author. The Corresponding Author shall: (i) ensure each Co-Author complies with all relevant provisions of this Publication Agreement, including those relating to confidentiality, performance and standards, as if a party to this Publication Agreement; and (ii) remain primarily liable for all acts and/or omissions of each such Co-Author.
\n\nThe Corresponding Author agrees to indemnify and hold IntechOpen harmless against all liabilities, costs, expenses, damages and losses and all reasonable legal costs and expenses suffered or incurred by IntechOpen arising out of or in connection with any breach of the aforementioned representations and warranties. This indemnity shall not cover IntechOpen to the extent that a claim under it results from IntechOpen's negligence or willful misconduct.
\n\n4.2 Nothing in this Publication Agreement shall have the effect of excluding or limiting any liability for death or personal injury caused by negligence or any other liability that cannot be excluded or limited by applicable law.
\n\n5. TERMINATION
\n\n5.1 IntechOpen has a right to terminate this Publication Agreement for quality, program, technical or other reasons with immediate effect, including without limitation (i) if the Corresponding Author or any Co-Author commits a material breach of this Publication Agreement; (ii) if the Corresponding Author or any Co-Author (being an individual) is the subject of a bankruptcy petition, application or order; or (iii) if the Corresponding Author or any Co-Author (being a company) commences negotiations with all or any class of its creditors with a view to rescheduling any of its debts, or makes a proposal for or enters into any compromise or arrangement with any of its creditors.
\n\nIn case of termination, IntechOpen will notify the Corresponding Author, in writing, of the decision.
\n\n6. INTECHOPEN’S DUTIES AND RIGHTS
\n\n6.1 Unless prevented from doing so by events outside its reasonable control, IntechOpen, in its discretion, agrees to publish the Chapter attributing it to the Corresponding Author and any Co-Author.
\n\n6.2 IntechOpen has the right to use the Corresponding Author’s and any Co-Author’s names and likeness in connection with scientific dissemination, retrieval, archiving, web hosting and promotion and marketing of the Chapter and has the right to contact the Corresponding Author and any Co-Author until the Chapter is publicly available on any platform owned and/or operated by IntechOpen.
\n\n6.3 IntechOpen is granted the authority to enforce the rights from this Publication Agreement, on behalf of the Corresponding Author and any Co-Author, against third parties (for example in cases of plagiarism or copyright infringements). In respect of any such infringement or suspected infringement of the copyright in the Chapter, IntechOpen shall have absolute discretion in addressing any such infringement which is likely to affect IntechOpen's rights under this Publication Agreement, including issuing and conducting proceedings against the suspected infringer.
\n\n7. MISCELLANEOUS
\n\n7.1 Further Assurance: The Corresponding Author shall and will ensure that any relevant third party (including any Co-Author) shall, execute and deliver whatever further documents or deeds and perform such acts as IntechOpen reasonably requires from time to time for the purpose of giving IntechOpen the full benefit of the provisions of this Publication Agreement.
\n\n7.2 Third Party Rights: A person who is not a party to this Publication Agreement may not enforce any of its provisions under the Contracts (Rights of Third Parties) Act 1999.
\n\n7.3 Entire Agreement: This Publication Agreement constitutes the entire agreement between the parties in relation to its subject matter. It replaces and extinguishes all prior agreements, draft agreements, arrangements, collateral warranties, collateral contracts, statements, assurances, representations and undertakings of any nature made by or on behalf of the parties, whether oral or written, in relation to that subject matter. Each party acknowledges that in entering into this Publication Agreement it has not relied upon any oral or written statements, collateral or other warranties, assurances, representations or undertakings which were made by or on behalf of the other party in relation to the subject matter of this Publication Agreement at any time before its signature (together "Pre-Contractual Statements"), other than those which are set out in this Publication Agreement. Each party hereby waives all rights and remedies which might otherwise be available to it in relation to such Pre-Contractual Statements. Nothing in this clause shall exclude or restrict the liability of either party arising out of its pre-contract fraudulent misrepresentation or fraudulent concealment.
\n\n7.4 Waiver: No failure or delay by a party to exercise any right or remedy provided under this Publication Agreement or by law shall constitute a waiver of that or any other right or remedy, nor shall it preclude or restrict the further exercise of that or any other right or remedy. No single or partial exercise of such right or remedy shall preclude or restrict the further exercise of that or any other right or remedy.
\n\n7.5 Variation: No variation of this Publication Agreement shall be effective unless it is in writing and signed by the parties (or their duly authorized representatives).
\n\n7.6 Severance: If any provision or part-provision of this Publication Agreement is or becomes invalid, illegal or unenforceable, it shall be deemed modified to the minimum extent necessary to make it valid, legal and enforceable. If such modification is not possible, the relevant provision or part-provision shall be deemed deleted.
\n\nAny modification to or deletion of a provision or part-provision under this clause shall not affect the validity and enforceability of the rest of this Publication Agreement.
\n\n7.7 No partnership: Nothing in this Publication Agreement is intended to, or shall be deemed to, establish or create any partnership or joint venture or the relationship of principal and agent or employer and employee between IntechOpen and the Corresponding Author or any Co-Author, nor authorize any party to make or enter into any commitments for or on behalf of any other party.
\n\n7.8 Governing law: This Publication Agreement and any dispute or claim (including non-contractual disputes or claims) arising out of or in connection with it or its subject matter or formation shall be governed by and construed in accordance with the law of England and Wales. The parties submit to the exclusive jurisdiction of the English courts to settle any dispute or claim arising out of or in connection with this Publication Agreement (including any non-contractual disputes or claims).
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