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Preface
The last three decades have witnessed dramatic strides in our ability to successfully treat and manage infection with the human immunodeficiency virus (HIV). The ongoing development and availability of more effective and better-tolerated antiretroviral (ARV) medications have contributed to this, resulting in virologic suppression in a majority of patients taking ARVs. The rollout of certain ARVs for pre-exposure prophylaxis or “PrEP” represents an example of successful innovation to reduce the number of new infections. However, we continue to see new increasing numbers of new infections, particularly in certain patient populations, such as young men who have sex with men (MSM) and those of Hispanic or African descent. Coinfection with other viruses, such as hepatitis C virus (HCV), addressed later in this book, represents a significant ongoing challenge, especially as it relates to the opioid epidemic. End organ damage, such as liver cirrhosis and failure in this case, but also cardiovascular and renal disease, and malignancy, may now present more of an existential threat to individuals living with HIV, even those with wellcontrolled infection. To this end, this book will explore the entire gastrointestinal tract and describe its relationship with HIV, detailing the myriad potential manifestations related to opportunistic infections, medications, and HIV-related malignancy, among others. Chapters are organized by organ system within the GI tract, with liver diseases covered in two separate chapters, one focusing on viral hepatitis.
It is our hope that the information summarized in this work will help guide clinicians who care for this patient population in their continued efforts to improve quality and extend survival in those living with HIV infection.
Farmington, CT, USA
Lisa M. Chirch, MD, FIDSA
Contributors
Nishaal Antony, MD Division of Infectious Diseases, Georgetown University Medical Center, Washington, DC, USA
Henry Anyimadu, MD, FACP, FIDSA, AAHIVS Division of Infectious Diseases, The Hospital of Central Connecticut, New Britain, CT, USA
Gayle P. Balba, MD Division of Infectious Diseases, Georgetown University Medical Center, Washington, DC, USA
Sarah Banks, MD Division of Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT, USA
Jack Fuhrer, MD Division of Infectious Diseases, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
James H. Lewis, MD, FACP, FACG Division of Gastroenterology, Georgetown University Medical Center, Washington, DC, USA
Rahul Mahapatra, DO SUNY Upstate Medical University, Syracuse, NY, USA
Sidney Olefson, MD, MBA Division of Gastroenterology & Hepatology, University of Connecticut School of Medicine, Farmington, CT, USA
Ann Palmer, MD Division of Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT, USA
Alexander Perelman Division of Gastroenterology, University of Connecticut School of Medicine, Farmington, CT, USA
Kavita Prabhakar, MD Division of Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT, USA
Ramona Rajapakse, MD, FRCP Division of Gastroenterology and Hepatology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
Houman Rezaizadeh Division of Gastroenterology, University of Connecticut School of Medicine, Farmington, CT, USA
Contributors
Isaiah P. Schuster, MD Division of Gastroenterology and Hepatology, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, USA
Mary Snayd Division of Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT, USA
Haleh Vaziri, MD Division of Gastroenterology & Hepatology, University of Connecticut School of Medicine, Farmington, CT, USA
Ulysses Wu Division of Infectious Diseases, Saint Francis Hospital and Medical Center, Hartford, CT, USA
Chapter 1 Disorders of the Esophagus
Alexander Perelman and Houman Rezaizadeh
Chapter content: In this chapter we will focus on the esophageal manifestations of HIV infection. We will review clinical features of common OIs and noninfectious complications of HIV, as well as diagnostic and therapeutic approaches for clinicians.
Clinical Presentation
The clinical presentation of esophageal disease is frequently nonspecific, thus making it difficult to decipher common esophageal disorders such as gastroesophageal reflux and esophageal dysmotility from HIV-associated complications. In patients who are adherent to their ART regimens, viremia is often undetectable, and upper GI symptoms tend to be unrelated to their HIV-positive status [11]. Symptoms most commonly associated with the use of ART relating to the GI tract include nausea, vomiting, diminished appetite, and weight loss. Pancreatitis had previously been reported but is less common with newer regimens.
Patients commonly present with complaints of dysphagia, odynophagia, and retrosternal pain. Typically, there is no clear association between symptoms and the underlying pathology. Although a prior study found an association with odynophagia and esophageal ulceration, the underlying cause of the ulcer was difficult to identify [12].
A. Perelman (*) · H. Rezaizadeh
Division of Gastroenterology, University of Connecticut School of Medicine, Farmington, CT, USA
L. M. Chirch, J. Ivanaviciene (eds.), HIV and GI Tract Complications, Clinical Gastroenterology, https://doi.org/10.1007/978-3-030-13377-1_1
A. Perelman and H. Rezaizadeh
Opportunistic Infections
Opportunistic infections of the esophagus are most commonly caused by fungi and viruses [11]. Although OIs can occur in patients with normal CD4 counts, as the cell population declines below 200 cells/mm3, OI incidence rates increase.
Esophageal Candidiasis
Esophageal candidiasis is the most common OI affecting the esophagus and frequently occurs concomitantly with oral thrush leading to localized infection without candidemia. Local infection predominates as Candida species prefer the keratinized squamous epithelium of the oral mucosa and esophagus [13]. Candida species most commonly seen in association with esophagitis is C. albicans; however, C. glabrata, C. dubliniensis, and C. krusei have also been isolated [14]. Manifestation of disease requires a two-step process, colonization and invasion. Up to 20% of healthy individuals are colonized with Candida species without clinical symptoms [15], with active infection occurring with waning immunity.
Clinical presentation includes dysphagia, odynophagia, and retrosternal pain, with or without concomitant oral thrush. (Endoscopy can be beneficial in making the diagnosis, but data support an empiric trial of fluconazole in patients suspected of having esophageal candidiasis [16]. If symptoms fail to resolve after the trial, endoscopic evaluation is warranted.)
The characteristic endoscopic findings of esophageal candidiasis are erythematous mucosa covered with plaque-like lesions ranging in color from white to yellow. The plaques are difficult to wash off, however can be brushed or biopsied for laboratory testing. The extent of disease can be described using endoscopic Kodsi criteria (Fig. 1.1) [17]. However, the degree of severity on endoscopy does not appear to correlate to the degree of immunosuppression [11]; thus patients with relatively normal CD4 cell counts may still experience severe candida esophagitis.
Failure to respond to fluconazole may be indicative of resistant organisms; in such instance, itraconazole, posaconazole, voriconazole, echinocandins, or intravenous therapy with amphotericin b deoxycholate is recommended. In patients with recurrent candida esophagitis, chronic suppressive treatment is currently recommended with 100–200 mg of fluconazole given three times per week [16] (Table 1.1).
Histoplasmosis
Histoplasma capsulatum is a dimorphic fungus present throughout the Midwestern United States and Central and South America [19]. The likelihood of developing
Fig. 1.1 Esophageal candidiasis Kodsi severity grading (a) Grade I, a few raised white plaques up to 2 mm in size without edema or ulceration. (b) Grade II, multiple raised white plaques greater than 2 mm in size without ulceration. (c) Grade III, confluent, linear, and nodular elevated plaques. (d) Grade IV, finding of grade III with increased friability of the mucous membranes and occasional narrowing of the lumen. (e) “White carpet” appearance, thick white plaque cover on esophageal mucosa circumferential narrowing the lumen. (f) Oral candidiasis, in which endoscopy can detect laryngopharyngeal candidiasis [17]
histoplasmosis and severity of illness directly correlate to the impairment of the immune system, particularly with CD4 cell counts below 200 cells/mm3. Gastrointestinal manifestations are common; however esophageal involvement is reported in only 3% [19, 20].
Dysphagia and odynophagia are the most common presenting symptoms. They can occur secondary to extrinsic compression of the esophagus in the settings of disseminated histoplasmosis resulting in profound lymphadenopathy [18, 20]. Symptoms may also occur from direct infection of the esophageal mucosa causing ulceration. The endoscopic appearance is nonspecific, requiring tissue biopsy to make the diagnosis in isolated cases. Gomori’s methenamine silver stain demonstrates the typical appearance of yeast organisms contained within macrophages, while urinary or serologic testing can be used to support the diagnosis [21, 22].
Therapy for mild to moderate disease consists of itraconazole for a period of at least 12 months. The dose is generally adjusted for interactions with ART agents and a goal serum concentration of greater than 1 μg/mL. Alternative regimens are available if patients are not able to tolerate itraconazole. In cases of severe disseminated disease, liposomal amphotericin B remains the drug of choice [23].
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Mycobacterium Species
Mycobacterial infections are OIs typically associated with significant decline in CD4 cell counts. Patients are at risk for infection with Mycobacterium tuberculosis (MTb) and Mycobacterium avium complex (MAC) for which prophylactic antibiotics are initiated once CD4 cell counts fall below 50 cells/mm3. Typically, both manifest as systemic and pulmonary disease with little involvement of the gastrointestinal tract [ 23 ]. However, patients suffering from pulmonary MTb infections have been reported to have esophageal symptoms secondary to erosion of mediastinal lymph nodes into the esophagus. In these cases, the mucosa may appear ulcerated or hypertrophic with a granulomatous appearance and possible formation of fistulas [ 11 ]. Treatment options are aimed at the underlying systemic infection and HIV with use of ART; if a fistula has developed, it may require endoscopic or surgical intervention.
Herpesviridae Family
Viral esophagitis is the most common OI affecting the esophagus after candida esophagitis. The Herpesviridae family of double-stranded DNA viruses are the most common pathogens with cytomegalovirus (CMV) being isolated most frequently, followed by herpes simplex virus (HSV) 1 and 2.
CMV
CMV esophagitis is the most common gastrointestinal manifestation second only to colonic infection [ 24 ]. Patients typically present with symptoms once CD4 cell counts fall below 100 cells/mm 3 and activation of the dormant virus occurs. Symptoms are difficult to distinguish from other causes of esophagitis, typically presenting as dysphagia, odynophagia, and epigastric pain. Patients may appear to be drooling and report a fear of food due to severe odynophagia likely from esophageal ulceration. Endoscopy is helpful in making the diagnosis. Although there are no stereotypical features of CMV esophagitis that have been identified in the literature, some suggest presence of multiple, shallow ulcers greater than 1 cm as being indicative of CMV infection [ 25 ]. Confirmation of the diagnosis continues to be a challenge with large numbers of biopsy samples necessary to identify the organism, with the highest yield coming from samples taken from the center of the ulcer. While modern immunohistochemical (IHC) techniques have improved yields, the same cannot be said for esophageal brushings and viral cultures [ 26 , 27 ]. The histopathologic features of
CMV esophagitis are similar to those from other anatomic sites, demonstrating giant cells with large nuclei and basophilic inclusions referred to as “owl’s eyes.”
CMV esophagitis therapy depends on the severity of disease and the ability of patients to tolerate an oral regimen. For patients with mild disease who are not taking ART, CMV-specific treatment can be delayed, while ART therapy plans are optimized. In individuals with severe disease limiting oral intake, an intravenous regimen with ganciclovir is recommended. Once symptoms improve, patients can be transitioned to an oral valganciclovir [23].
HSV
Similar to CMV esophagitis, HSV infections are very common in the general population with resultant dormant infection that reactivates with the decline of cellular immunity. Herpes simplex virus serotype 1 more commonly causes HSV esophagitis compared to serotype 2, with male patients more likely to be affected [28]. At presentations patients may have concomitant herpes labialis and oropharyngeal lesions [29]. The most common symptoms include dysphagia and odynophagia (fever and retrosternal chest pain can be present in 50% of patients).
Esophageal findings in HSV disease have a characteristic appearance with wellcircumscribed ulcers, smaller than 2 cm in size. The ulcer margins have a raised architecture resulting in the classic volcano-like appearance [30]. Unlike in CMV esophagitis, the diagnosis of HSV esophagitis can be made endoscopically and confirmed on histopathology, with highest yield samples coming from the ulcer edges.
On hematoxylin and eosin staining, multinucleated giant cells are seen with eosinophilic Cowdry A bodies suggestive of HSV infection. The diagnosis is further supported with IHC staining that is specific for HSV [31].
Treatment of HSV esophagitis is recommended for 2–3 weeks. Oral acyclovir, valacyclovir, and famciclovir are preferred agents for HSV esophagitis treatment. If oral regimen cannot be tolerated due to severity of symptoms, intravenous acyclovir may be used. Patients with confirmed HSV esophagitis who fail to respond to therapy may be infected with an acyclovir-resistant strain, in which case a foscarnet is recommended [23].
HHV-8
Unlike the previously discussed Herpesviridae members, human herpes virus 8 is not associated with esophagitis, but rather a low-grade vascular tumor. It was first described by the Hungarian dermatologist, Moritz Kaposi in 1872. Kaposi’s
A. Perelman and H. Rezaizadeh
sarcoma (KS) is classified into four variants which are all associated with HHV8 infection. One of these variants, AIDS-related Kaposi’s, is the most common gastrointestinal malignancy in AIDS patients [32]. These submucosal tumors consist of vascular spindle-shaped cells thought to originate from the endothelium [33].
Kaposi’s sarcoma is 20 times more common in AIDS-infected homosexual men than in AIDS-infected heterosexual patients after correcting for degree of immunosuppression. This is thought to be related to higher transmission rates of HHV8 in patients practicing anal and oral sex [32, 34]. It can be directly related to the degree of immunosuppression, however it can also be seen at any point during the course of HIV infection. Cutaneous lesions can be seen frequently in patients with concomitant visceral disease. The esophageal tumors of KS are likely to be asymptomatic but can manifest with mild nausea, vomiting, dysphagia, and catastrophic gastrointestinal bleeding.
Endoscopy reveals KS lesions with a distinct purple appearance; however biopsy is of low yield due to the submucosal location resulting in frequent falsenegative results. If adequate samples are obtained, staining for CD34, CD31, and LANA-1 (latency-associated nuclear antigen) helps detect later stages of disease [ 34 ].
Treatment of KS depends on the severity of HIV and KS tumor burden. In appropriate cases, ART alone may be considered. Prognosis is poor in most cases with chemotherapy focusing on palliation. Regimens usually consist of liposomal anthracycline with response rates of approximately 45% [32, 35].
Idiopathic Ulcer
Similar to CMV and HSV esophagitis, patients with idiopathic esophageal ulcers (IEUs) present with odynophagia, dysphagia, and retrosternal chest pain. It is more commonly seen in patients with CD4 cell counts below 50 cells/mm3 but may occur at any stage of disease. Those with severe symptoms may appear dehydrated and complain of weight loss secondary to food avoidance [11]. During endoscopy, IEUs can be confused for the ulcers of CMV and HSV but generally appear to be larger with deeper penetration into the muscularis propria layer with irregular margins [11, 36]. The diagnosis is alluded to the endoscopic appearance and failure to identify other causative agents on endoscopy and pathology. Some data suggest that HIV itself is the causative agent. A recent study found that in 75% of AIDS patients with IEUs, HIV was found on esophageal biopsy [36]. Treatment is aimed at controlling the viremia with the use of ART, while other authors suggest the use of steroids and proton pump inhibitors to optimize healing [37, 38].
Table 1.1 Common causes of esophagitis in patients with HIV
Clinical presentation Dysphagia, odynophagia, retrosternal pain, can present with concomitant oral thrush. Typically seen when CD4 <200 cells/ mm3
Diagnosis
Erythematous mucosa with white to yellow plaques covering a variable degree of the esophagus Spores and pseudohyphae
Treatment Oral fluconazole for 2–3 weeks. If unable to take oral, IV fluconazole is available
Dysphagia, odynophagia, retrosternal pain. Typically seen when CD4 <100 cells/mm3
Shallow, >1 cm, commonly result in strictures Basophilic nuclear inclusions “owl’s eyes”
Oral valganciclovir for 3–6 weeks. If not able to take oral, can use IV ganciclovir
Dysphagia, odynophagia, retrosternal pain. May have coexistent herpes labialis or oropharyngeal lesions. More common in men. Typically seen when CD4 <100 cells/mm3
Well-circumscribed “punched-out” appearance with heaped-up edges with a “volcano-like” appearance <2 cm Multinucleated giant cells with eosinophilic inclusions – Cowdry A bodies
Oral acyclovir or valacyclovir for 2–3 weeks. If not able to take oral, can use IV acyclovir resistant HSV may need foscarnet regimen
ART antiretroviral therapy, PPI proton pump inhibitors
Noninfectious Etiologies
Lymphoma
Dysphagia, odynophagia, retrosternal pain, dehydration, and weight loss. Typically seen when CD4 <50 cells/mm3
Large single or multiple deep ulcers penetrating to muscularis propria with inflamed irregular edges Large areas of necrosis with surrounding edema and infiltrating inflammatory cells
ART and acid suppression with PPI. Some data also support use of prednisone for 2 weeks
Isolated esophageal lymphoma is extremely rare accounting for less than 1% of primary lymphoma. Diffuse large B cell lymphoma is the more common type [39]. HIV-infected patient have a significant increased risk of developing lymphoma with risk for Hodgkin’s disease being 10 times greater than HIV-negative patients and non-Hodgkin’s disease greater than 100 times of uninfected patients [40]. Lymphoma typically involves distal part of the esophagus resulting in dysphagia as the most common presenting complaint [41]. In order to make the diagnosis of primary
A. Perelman and H. Rezaizadeh
Table 1.2 Dawson criteria. All five criteria must be met to make a diagnosis of primary gastrointestinal lymphoma [2]
Dawson criteria
No palpable superficial lymph nodes
Normal chest radiograph findings with no evidence of lymphadenopathy
Normal white blood cell (WBC) count
Predominant lesion within the GI tract, with lymph node involvement confined to the lymph node chain involved in drainage of that specific GI segment
No involvement of the liver or spleen
gastrointestinal lymphoma, the Dawson criteria (Table 1.2) must be met to ensure that the disease is confined to the GI tract [2]. Endoscopic findings are variable and nonspecific often with submucosal lesions yielding false-negative results on biopsy. Treatment options depend on the subtype of lymphoma, local confinement, and patients’ overall health status. Cyclophosphamide, doxorubicin, vincristine, and prednisone in combination with rituximab are often the first-line regimen that may be supplemented with external beam radiation in appropriate candidates [40, 41].
Non-AIDS-Defining Esophageal Cancer
Over the last few decades, the incidence of esophageal cancer has increased. This increase has been attributed to multiple factors including smoking, alcohol use, and the obesity epidemic. There does not appear to be a significant difference in esophageal cancer rates among patients with or without HIV infection. However, when comparing HIV-infected patients who also have AIDS, they appear to be at a slightly higher risk for esophageal cancer than the general population [42, 43].
Motility Disorders
It is difficult to estimate the true incidence of esophageal motility disorders in the general population. The best characterized disorder in the literature is achalasia with an incidence rate of 2 per 100,000 and a prevalence of 10 per 100,000 people [44, 45]. Achalasia is an uncommon condition that results from the loss of inhibitory innervation in the esophagus culminating in an aperistaltic esophagus with a hypercontracted lower esophageal sphincter. Some data support that an initial viral insult is the trigger for the disease. There is a paucity of data on motility disorders in patients with HIV, with some of the first reports coming from Barrow et al. when they reported two previously healthy male patients who were diagnosed with achalasia after acquiring HIV [46]. However, this is more likely to represent a correlation rather than a causative relationship.
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23. Adolescents, P.o.O.I.i.H.-I.A.a. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2018.
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Chapter 2 HIV and the Stomach
Sidney Olefson and Haleh Vaziri
HIV
and the Stomach
Human immunodeficiency virus (HIV), first characterized in the 1980s, targets various cell types of the innate and adaptive immune system. According to UNAIDS, an estimated 34 million people were living with the virus in 2010, an increase of 17% since 2001 [1]. The rate of new infection is thought to have peaked in 1997 [1]. After sexual transmission via genital mucosa, the virus targets dendritic cells in the lamina propria that fuse with CD4+ lymphocytes and spread through the lymphatic system [2]. The viral envelope protein, glycoprotein 120, then binds to the CD4 molecule, allowing entry inside of the cell via a surface chemokine receptor, CCR5 or CXCR4. This is followed by a rapid plasma viremia, as the virus metastasizes to lymph nodes. Ultimately, viremia leads to the depletion of CD4+ T lymphocytes, which renders the host susceptible to opportunistic infections.
The mucosal surface of the healthy gastrointestinal tract forms an anatomical and physiological barrier against microorganisms, but the GI tract of HIV-infected individuals has been shown to be susceptible to enteropathy [3]. Proposed mechanisms include direct virotoxic effect from HIV on the enterocytes, structural weakness via tubulin depolymerization and decreased ability to maintain ionic balance, and deleterious effect on enterocyte differentiation [4]. Furthermore, the virus is thought to activate local immune factors via proliferation of pro-inflammatory cytokines, IFNγ, IL-6, and IL-10, found to be overexpressed in gastrointestinal lamina propria of HIV-infected patients [5]. Also, the GI mucosa contains a large segment of the overall pool of CD4+ lymphocytes, and these are depleted in HIV-infected patients [6].
S. Olefson · H. Vaziri (*)
Division of Gastroenterology & Hepatology, University of Connecticut School of Medicine, Farmington, CT, USA
L. M. Chirch, J. Ivanaviciene (eds.), HIV and GI Tract Complications, Clinical Gastroenterology, https://doi.org/10.1007/978-3-030-13377-1_2
11
S. Olefson and H. Vaziri
The stomach serves as an initial site of immune-epithelial interactions. The immune system encompasses both innate (neutrophil, macrophage, dendritic cells) and adaptive components (B- and T-cell lymphocytes) [7]. Furthermore, the microbiome of the proximal gut, with a colony count of 101 to 103 CFU/g, appears to differ between immunocompetent and immunodeficient individuals [7].
In a study of the microbial contents of gastric fluid, von Rosenvinge et al. found reduced bacterial diversity in patients who were exposed to antibiotics, were HIVinfected, or had gastric fluid pH above 4, leading to decreased numbers of Prevotella, Fusobacterium, and Leptotrichia species and increased quantities of Lactobacillus species [8].
Opportunistic Infections
Introduction
Opportunistic infections (OIs) of the GI tract, defined as infections which are more frequently seen in the presence of immunosuppression, are frequently encountered in patients infected with HIV [9]. In fact, the GI tract served as the first site of AIDSdefining illness in 18.7% of patients in one series [10]. Over time, the rates of OIs of the GI tract declined with the use of highly active antiretroviral therapy (HAART) [10]. One study found the incidence of GI-related OIs to be 91% in patients who are not on HAART, 57% in patients on HAART without a protease inhibitor, and 30% in patients taking HAART with a protease inhibitor [10]. In the same study, the use of HAART paralleled the rise of CD4 counts and was inversely correlated with viral load measurements.
Cryptosporidium
Cryptosporidium, a protozoa, is an important cause of diarrhea in both immunocompetent and immunocompromised individuals. It commonly affects the small intestine but can involve the entire GI tract, including the biliary system [11]. Involvement of the stomach is thought to be due to retrograde flow from the small intestine [12]. Infection of the stomach with Cryptosporidium typically presents with diarrhea but can also cause vomiting, weight loss, and abdominal pain [12].
In patients with gastric cryptosporidiosis, diagnosis is frequently made via gastric biopsy rather than stool examination. The organisms are often found in the luminal border of the cells and less commonly in the columnar region [12]. One should obtain several biopsies as the distribution is typically patchy, with heavy infestation in one area but not adjacent to it.
In a case series of 16 patients, only 2 were diagnosed via stool testing alone [13]. Histologic distribution was most commonly seen in the antrum/pylorus area with no involvement of the fundus or cardia which has implication for targeting biopsies [12]. Changes seen on histology include non-specific inflammation, epithelial reactive
changes, foveolar epithelial damage, and glandular atrophy [12, 14]. In one case series of eight patients with this infection, endoscopic examination revealed no mucosal changes in half and inflammatory changes (hyperemia, edema) in the other half [12]. Treatment of gastric cryptosporidiosis can be challenging. Antiviral therapy is critical to boost the host’s immune system response. However, antiparasitic medication is sometimes required for patients with debilitating symptoms. A compassionate use trial evaluating the use of nitazoxanide in 365 patients for a median treatment duration of 62 days showed a 59% sustained clinical response [15]. However, a Cochrane meta-analysis of 7 trials that included 130 HIV-positive patients found no difference in duration or frequency of diarrhea when this agent was compared to placebo among HIV-positive patients [16]. In an open-label trial of patients who had failed nitazoxanide, combination therapy with paromomycin and azithromycin showed improvement of symptoms and decreased parasite stool shedding [17].
Leishmania
Visceral leishmaniasis (VL) may occur in patients with advanced HIV/AIDS, but involvement of the GI tract with gastric involvement is limited to small case series. One case series reported gastric involvement in 75% of patients with gastrointestinal involvement [18]. Abdominal pain, gastrointestinal hemorrhage, and dysphagia are commonly reported symptoms [18]. Diagnosis can be difficult as observation of serum amastigotes is only observed in 50% of patients infected with VL and HIV [19]. Furthermore, serology is only positive in 40–50% of co-infected cases [20]. Treatment has been reported with liposomal amphotericin B and with N-methylglutamine antimoniate but has limited reported efficacy [18, 20].
Cytomegalovirus (CMV)
Prior to HAART, about 40% of HIV-infected patients were expected to have a CMV-related condition within their lifetime [21]. In the HAART era, the incidence of CMV has decreased substantially [21]. Although commonly discovered in the colon and esophagus, CMV infection has also been observed in the stomach, typically described in patients with advanced AIDS [22]. Symptoms include abdominal pain, GI bleed, nausea, and vomiting, but some patients may be asymptomatic [22]. CMV gastritis mostly manifests as a gastric ulcer. In a study of symptomatic HIV patients who underwent endoscopic examination, 8 of 16 (50%) patients who were found to have peptic ulcers at endoscopy had CMV infection compared with 1 of 20(5%) who did not have an ulcer [23]. Infected patients usually have multiple ulcers [22]. Ulceration is thought to occur through a vasculitic process. Biopsies should be obtained from the ulcer edge and base. Polymerase chain reaction will improve the diagnostic yield [23]. Ganciclovir given intravenously is often effective at eradication. The duration of treatment is usually 2–3 weeks, but one may opt to prolong the therapy with oral valganciclovir if ongoing severe immunosuppression is expected [24].
S. Olefson and H. Vaziri
Cryptococcus
Cryptococcus neoformans typically affects the central nervous system or pulmonary system, can rarely involve the GI tract. In the 2 published case series of 95 patients with cryptococcal infection, no case of gastrointestinal involvement was reported [25, 26]. The clinical presentation may vary from asymptomatic to intractable nausea and vomiting to peritonitis [27–29].
Gastric mucosal biopsies have a limited value in making the diagnosis due to the lack of specificity of the mucin stains for cryptococcus [28]. Endoscopic features are also non-specific and may include inflammatory polyps and erosions [30]. Treatment of extrapulmonary and extrameningeal infection is managed with the induction of amphotericin B lipid complex given intravenously in combination with oral flucytosine. After at least 2 weeks of successful induction therapy, these can be discontinued, and maintenance therapy with fluconazole 400 mg/day can be initiated for a minimum of 8 weeks [31].
Syphilis
Syphilis is a sexually transmitted disease due to infection with the bacterium, Treponema pallidum, that has seen a rise in incidence coinciding with the HIV/ AIDS epidemic [32]. In a systematic review of 52 cases of gastric syphilis, the presenting symptoms included epigastric pain/fullness (92%) and gastric bleeding (35%) [33]. Unfortunately, the majority of these patients had no historical (87%) or physical exam features (56%) consistent with syphilis.
Endoscopic findings from that study revealed multiple ulcerations (48%), nodular mucosa (26%), erosions (24%), large ulcers (24%), thickened folds (17%), narrowing and rigidity (17%), and mass lesions (2%) with the antrum being the most affected part of the stomach [33]. Histologic examinations was notable for spirochetes, seen on silver staining along with elastic and reticulum fibers [32]. In addition, findings consistent with endovasculitis have been reported including arterial wall thickening, perivascular cell infiltrate, and diffuse lymphocytic and plasmacytic infiltrate [34].
Serologic testing includes nontreponemal tests, such as the Venereal Disease Research Laboratory (VDRL) antibody and rapid plasma reagin (RPR) in addition to the more specific fluorescent treponemal antibody absorption (FTA-Abs) and treponema pallidum hemagglutination (TPHA) test [35]. Active infection is generally represented by a high RPR or VDRL titer which resolved with effective therapy. Treponemal serology remains positive despite adequate therapy, although false negative can be observed in a variety of circumstances including severe immunosuppression.
Rapid resolution of symptoms has been reported in 83% of patients who were treated with intravenous penicillin [33]; however, some may require surgical intervention for complications of gastric syphilis including gastric perforation, obstruction, or chronic aspiration.
Helicobacter pylori
Worldwide prevalence of Helicobacter pylori (HP) ranges from 5% in Northern European children to over 80% in certain regions of Asia [36]. It is transmitted via gastro-oral and fecal-oral routes. In a systematic review by Nevin et al., the prevalence of HP was found to be higher in HIV-negative compared to HIV-positive patients [36]. The HP prevalence is lower in patients with advanced immunodeficiency [36]. Furthermore, gastric ulcers in HIV-positive patients were found to be more commonly related to cytomegalovirus (CMV) than HP [37].
Several theories have been proposed to explain these findings. AIDS is associated with gastric hypoacidity that leads to a lower maximal acid secretion and higher fasting gastrin levels [38] which renders the environment less optimal for HP colonization. In addition, the immunocompromised state of HIV increases the risk of infection by other pathogens which may compete with HP and decrease the likelihood of its colonization [37]. CD4+ lymphocytes play a role in the pathogenesis of HP-related gastritis through unclear mechanisms which might explain why their depletion decreases the chance of colonization [37, 39].
It has been suggested that HP organism increases its access to nutrients by increasing the permeability of gastric mucosa. The diminished inflammatory response in HIV patients interferes with this process [36]. Antibiotics are routinely prescribed for prophylaxis against OIs in patients with advanced HIV/AIDS. While monotherapy has not been shown to be able to eradicate HP, it probably serves to decrease the number of organism, and therefore the absence of detection in observational studies may be related to lower HP counts rather than elimination [36, 37]. The incidental elimination of HP due to widespread antibiotic use in these patients may also play a role in the lower rate of HP prevalence.
As HIV therapy has improved, the rate of HP infection has increased in this population. In a cohort study, the rate of HP infection, detected by mucosal biopsies, increased from 11% in the “pre-HAART” era (1991–1994) to 39.6% in the “recent HAART” era (2005–2006) [40]. Similarly, rates of gastric ulcer disease increased from 3.8% to 8.3%. Interestingly, the rate of HP infection is still lower in HIV patients in the HAART era compared to HIV-negative controls [41].
Diagnosis
Data regarding the accuracy of both invasive and noninvasive methods of establishing the diagnosis of HP in HIV patients are sparse. A single-center study of 60 HIV patients showed no difference in rate of positivity between C13 breath testing and HP-immunoglobulin positivity (23% and 20%, respectively) which did not differ even when stratified by HIV stage, CD4 cell count, and HIV RNA level [42].
However, both of these methods have limitations in this population. Serology is not specific to active infection and may not be accurate in immunocompromised hosts. Breath testing can be falsely positive in the HIV population given the possibil-
S. Olefson and H. Vaziri
ity of colonization of urease-positive bacteria in the upper GI tract [42]. It is therefore generally recommended to have at least two forms of testing to detect HP infection.
Treatment
Treatment of HP in the HIV population can be particularly challenging. In a prospective study of 353 patients, the overall rates of resistance were higher in HIVpositive vs HIV-negative patients (69.8% vs 51.5%, p = 0.002) [43]. In this study the resistance rates for levofloxacin- and metronidazole-based regimens were significantly higher among HIV-positive patients vs controls. While overall clarithromycin resistance was not different between the groups, it was higher in HIV patient with low CD4 counts (CD4 was <200 cells/μL) [43]. These differences may be explained by high rates of use of fluoroquinolone for infectious diarrhea, urinary tract infection, or pneumonia and macrolides for chemoprevention of Mycobacterium avium complex (MAC) in patients with advanced HIV.
Another challenging aspect of HP eradication in HIV patients is the possibility of drug-drug interaction. PPIs can alter pharmacokinetics of antiretrovirals (ARVs). This can alter the gastric acidic environment and affect the absorption of particular drugs. For example, rilpivirine, a non-nucleoside reverse transcriptase inhibitor, should be given with a meal to encourage gastric acid secretion. Its use with a PPI is contraindicated unless it is markedly spaced from administration to avoid excessive elevation of intragastric pH [44].
Another notable phenomenon observed after HP eradication among patients with HIV is immune reconstitution, defined as an increase in CD4 and CD8 counts. In a prospective study of 26 patients diagnosed with HP infection by breath testing, 11 were treated for HP, while the other 15 refused the therapy. The treated group experienced significant increases of CD4 and CD8 cells at 3 months after therapy, gradually peaking at 12–18 months. The untreated group experienced no change in CD4 or CD8 cells [45]. This immune reconstitution effect may have been driven by stimulation of monocytes and macrophages by HP, which can lead to expression of CCR5 on T cells, a cellular target of HIV. Thus, elimination of HP when identified may assist with strengthening of the immune system and provides additional evidence for aggressive treatment.
Malignancy
Introduction
Gastric cancer is the fourth most common cancer and second cause of cancer death in the world [46]. Its distribution varies by region but is highest in Japan and Korea, estimated to be 42 per 100,000 per year in men and 18 per 100,000 per year in women [46]. Established risk factors include HP infection, smoking, alcohol use,
and diet [47]. The immune system seems to play a role in carcinogenesis. In a Brazilian study of 528 HIV-infected patients with dyspepsia, gastric malignancies were observed in 3 (1.8%) patients, all of whom had CD4 counts under 200/μl [48].
Kaposi’s Sarcoma
Kaposi’s sarcoma (KS), a tumor of vascular endothelium origin, is a relatively common malignancy in patients with immunodeficiency. Visceral involvement, while uncommon overall, is more frequently seen in HIV patients, seen in 12–24% of HIV-KS cases [49, 50]. Of these cases, gastrointestinal involvement was observed in 11–19% [49, 50]. The causative agent is human herpesvirus-8 (HHV8), which can be identified in every case of the disease [51].
The incidence of KS among HIV/AIDS patients has declined from 25.6 per 100 person years in the early 1990s to 7.5 by 1996–1997 period likely due to the introduction of HAART [52]. Several forms of KS have been described [53]. The first one of the three non-HIV-associated forms has been observed in elderly men in Europe. The second type which also is non-HIV related, is associated with lymphadenopathy and is aggressive. The typical cutaneous lesions of KS are not commonly seen in this form. The third type is associated with organ transplant recipients and frequently has both visceral and cutaneous involvements. The fourth type which is associated with HIV/AIDS is the most common subtype worldwide. Its incidence in the United States was 0.3 per 100,000 before the AIDS epidemic (1973–1978) but peaked around 8.9 per 100,000 between 1989 and 1991 [54]. Cases of HIV-related KS occur predominantly in young men with an average age of onset at 39.8 years (81.5%) [55].
The risk of KS in HIV patients varies by mode of HIV transmission. When compared with the general population, the risk of KS is 13,000-fold greater after acquiring HIV through needles and 106,000-fold higher when acquired through male homosexual intercourse [56].
Histologically, all of the above forms are indistinguishable from each other, and they are characterized by presence of vascular clefts and spindle cells.
The presentation of gastric KS is variable. In a report of 27 cases who were diagnosed from 1428 endoscopies in a Brazilian center between 1999 and 2009, most were asymptomatic (81.5%) [55]. In symptomatic patients, abdominal pain, nausea, vomiting, bleeding, mechanical obstruction, and bowel perforation have been reported. The stomach was the primary site of GI involvement (55%) followed by multi-site involvement: esophagus/stomach/duodenum (25.9%) and stomach/duodenum (7.4%) [55]. The level of immunodeficiency was severe in this study with a mean CD4 count of 136 cell/mm3 and high viral load of 117,000 copies/ml. Fortyfive percent of patients were not on HAART. These results support the association between immunosuppression and KS.
Gastric involvement by KS can have one of the three endoscopic appearances: maculopapular lesions (type 1), polypoid lesions (type 2), and volcano-like lesions (type 3) [55]. In the above endoscopic case series of HIV patients with upper GI KS, most lesions were under 1 cm. Of the 55% of patients who were on HAART, the average duration of treatment was 12.6 weeks which may have had an impact on the
S. Olefson and H. Vaziri
size of discovered lesions [55]. Biopsy is essential to make the diagnosis given the heterogeneous endoscopic appearance, but the mucosal biopsy only yields a diagnosis in 15–23% of cases [52]. Endoscopic ultrasound-guided biopsies are frequently required to obtain submucosal tissue to make the diagnosis.
KS has spindle cell morphology and is frequently found in the submucosal layer in the proximity to hemosiderin-laden macrophage deposits causing a dark red appearance [52, 57].
Increased concentration of extracellular HIV-1 Tat protein foments a favorable growth environment for these spindle cells [57]. Yet, the presence of spindle cells alone is not pathognomonic for KS since these cells can also be seen in other types of tumors such as gastrointestinal stromal tumor, spindle cell melanoma, and angiosarcoma [54]. HHV8 latency-associated nuclear antigen, which helps viral DNA to attach to host genome, is considered a confirmatory immunohistochemical stain with reported 95% sensitivity and 100% specificity [58]. Other cited biomarkers include CD34 and CD117 but overlap with other tumors making them less specific for diagnosis [52].
The general approach to management of KS in HIV-infected patients, regardless of its location in the GI tract, begins with the initiation of HAART if not already started. This inhibits the production of the aforementioned Tat protein, which is important for both HIV replication and KS spindle cell growth [57]. Systemic chemotherapy may be required in some cases. Pegylated liposomal doxorubicin (PLD) has been studied in these patients because of the theoretical selective drug accumulation in KS cells. In a randomized open-label trial of 28 HIV-positive patients with KS, the response rate at 48 weeks was 20% in HAART-alone group versus 76% in patients who were treated with PLD in addition to HAART [59].
Lymphoma
The stomach is a rare extranodal site for primary non-Hodgkin lymphoma in patients with HIV [60]. The incidence of GI NHL in HIV patients has dropped significantly since the advent of HAART [61]. In Canada, the incidence has declined from 3.86 per 100,000 during 1985–1989 period to 0 in 2000–2004.
In a retrospective case series from India of patients with gastric lymphoma in which HIV status was not mentioned, the presenting symptoms were abdominal pain (34.8%), new-onset dyspepsia (27.9%), gastric outlet obstruction (16.3%), and gastrointestinal hemorrhage (14.0%) [62].
Prognosis for gastric lymphoma has been stratified to low-, intermediate-, and high-risk groups. Estimated 5-year event-free survival rates are 29%, 56%, and 70%, respectively. Risk factors associated with poor outcome include older age (>60 years), advance stage, poor performance status, and elevated LDH [63]. The prognosis of GI lymphoma may not be different between HIV and non-HIV patients [64]. Of 11 HIV patients with GI lymphoma in this series, 6 had primary gastric lymphoma.
It is worth noting that a correlation between hepatitis C virus (HCV) and mucosaassociated lymphoid tissue (MALT) lymphoma has been reported [65]. In a study of 25 patients with chronic HCV infection and gastric MALT lymphoma, HCV RNA was detected in 28% of studied patients [65].
Full discussion of all available modalities for treatment of gastric lymphoma is beyond the scope of this review. In general, it is recommended to test for and eradicate HP, with reported complete remission rates of gastric lymphoma of 50–80% in patients whose infections have been eradicated [66, 67]. These open-label trials do not specify HIV status of the included participants. In cases where patients fail to respond or progress despite HP eradiactaion, patients are generally offered chemotherapy or local radiation therapy (RT) [68].
Single-agent rituximab has shown promising results in patients with gastric MALT lymphoma (HIV status was not mentioned in this study) who have failed RT [69]. In patients co-infected with HCV that has not yet been eradicated, one retrospective analysis found a response rate among 45 patients with MALT lymphoma of 73% and a 1-year overall survival rate of 75% [70]. This suggests that the use of direct-acting antivirals in co-infected patients with MALT lymphoma may improve outcomes.
Gastric Adenocarcinoma
In contrast with other malignancies associated with immunosuppression, gastric adenocarcinoma has not been shown to be more prevalent in the HIV compared to non-HIV population [54]. In a prospective case-control study from Zambia between 2010 and 2012 of patients who were suspected to have gastric cancer by endoscopy and dyspeptic controls without mucosal abnormalities by endoscopy, the prevalence of HIV infection was not statistically different between the group with suspected and confirmed gastric cancer and the control group with dyspepsia and no mucosal abnormalities [46]. One possible explanation for the lack of signal in the HIV population may be related to the lower observed frequency of HP infection, a strong risk factor for gastric cancer [71].
Interestingly, intestinal metaplasia (IM), the precursor lesion for gastric adenocarcinoma, may be seen more frequently in HIV-positive compared to HIV-negative patients. In a recent cross-sectional study evaluating the utility of confocal laser endomicroscopy for detection of gastric premalignant lesions, 41 of 68 (60.3%) asymptomatic HIV-infected patients had IM compared to 8 of 22 (36%) of HIVnegative controls, although this did not reach statistical significance [72].
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pidettiin rippisaarna, josa vanhempi väki ynnä niiden nuorukaisten kanssa, jotka christillisyydensä tiedosa havattiin niin eistyneiksi, että he taittiin laskea Pyhälle Ehtoolliselle, tätä Sakramenttia nautitseen valmistettiin. Sitten seurasi tavallinen Jumalan palvelus ja sen lopuksi Pyhän Ehtoollisen jakaminen, niinkuin tavallinen on. Sitten viimmeseksi vihittiin kuulutetut parikunnat, ja käytiin kirkkosaarella kuolleet multaamasa. Paljo oli niinmuodon papeilla toimitettavana näisä kinkeritiloisa, joita tämänki Seurakunnan aluella oli 8. — Laiskuus ja huolettomuus luvun harjotuksisa rangastiin kovasti näisä kinkereisä. Erinomattain mainitaan Herr' Eerikkiä kovaksi. (Herra pantiin muinan ristintänimen edellä, ja niin kuttuttiin opettajia. Herr' Eerikki, Herr' Simuna, Herr' Iisakki, Herr' Juhannes jne. Sukunimestä ei sillon tiettykään.) Tämän Herr' Eerikin kinkeriä pelkäsit kaikki laiskat ja huonolukuset; sillä heillä edessä seiso penkkiin paneminen, joka sillä tavalla tapahtui että kuritettava pantiin vattallensa penkiin, tröiyn ja liivin riisuttua. Lukkari kävi ulkoa paksut vittat, jotka sinne edeltäpäin olit varustetut, ja alkoi heillä selkää muokata. Pappi seisoi vieressä ja manasi sekä kurittajata että kuritettavata; kurittajata urhollisuuteen kuritustyösänsä ja kuritettavata laiskuuden välttämiseen ja vasta-uutisen vireyden osottamiseen. Muutaman Hulkkosen muistellaan useen Herr' Eerikiltä laiskuuden tähden penkkiin pannuksi. Tämä mies, ehkä muuten näsäviisas ja komppasananen, oli aivan typerä lukunsa suhteen. Kerran joutu hän taas muutamasa kinkeritilasa Herr' Eerikin käsiin, joka puhutteli häntä näin: "Mitä sinä vanha laiska nyt sitte viime kinkerin olet oppinut: oletko sinä nyt viriämpi ollut?" — Muuan kinkeriväestä lausui tähän: "Wähän on taittu parata, eipä se siltä ole näyttänyt." — Hulkkonen nähden ittensä kokonaan sorretuksi, takasi: "Takamäki vaiti! on tässä eessäi tekemistä." Herr' Eerikki otti hänen kohta koetuksen alle josa Hulkkonen taas tuli ymmälle, I muuttu A:ksi
ja L muuttu Ä:si — Tässä suuttu kohta Herr' Eerikki, pani kypärän
kallellensa ja huusi lukkarille: "Pane laiska penkkiin." Lukkari tiesi kohta velvollisuutensa, ryhtyi miestä niskaan ja pani hänen penkkiin vatsallensa. Nyt meni hän ulos vittoja noutamaan; vaan joko Hulkkonen ne lie edeltäpäin korjannut, eipä niitä nyt löyttykään. Lukkari viipy kauvan ulkona niitä hakemasa. Aika kävi pitkäksi penkkiin pannulla. Hän huusi: "Jo nousen, hyvä herra, kerrassa nousenni" ja samasa hyppäsi hän ylös ja juoksi suksilleen, jotka sitte veivät hänen kauas papin silmistä. Näin pääsi hän tällä kerralla kurittajansa käsistä. — Tämä sama Hulkkonen kulki kerran kaupungisa. Siellä löysit hänen merimiehet ylen typeräksi ja aloit pilata häntä. Ne kysyit: "Kuules, pohjanmaan vaari, mikä tuuli se on joka taivaasta puhaltaa suoraan alas maan päälle?" Tähän vastasi Hulkkonen: "No eikö vanhat merimiehet tuota tää; napatuuli hän se on."
Wuonna 1787 saivat tämän Seurakunnan asujamet kappelioikeuden ja papin luoksensa. Ehkä asuvia siihen aikaan mainitaan rehellisiksi ja hyviksi, niin osottaa kuitenkin vanhuuden muistot, että pahoja jo sillonki löytyi. Muuan Tapio, jonka talo vasten tahdonsa pappilaksi senaikasilta pitäjän herroilta laitettiin, vainosi pappia tänne ensin tultuansa, ikääskun se olis syy ollut tähän vallottamiseen. Tämä Tapio meni vainosansa niin kauvas, että hän poikinensa päätti papin surmataksensa. Siihen nähden menit he muuanna syysiltana ulos pirtistä ja panit pönkät oveen ja ikkonoihin, ettei kukaan pääsisi sieltä ulos. Sitten kävit he sisälle papin tykö, panivat hänen köysiin, kannoit hänen ulos rekeen, jonka eteen hevonen oli valjastettu ja lähit ajamaan ulos mettään häntä surmataksensa. Mutta pirttiväki saivat kaikeksi onneksi pönkan ikkunasta poistetuksi ja pääsit hätään, ennenkun murhatyö heiltä tuli täytetyksi. Tapio tuomittiin tästä työstä fangiuteen ijäksi päiväksi ja
poika kuudeksi vuodeksi. Isä kuuluu jo ammon kuolleeksi; pojan luultaan vielä elävän ehk' ei häntä sen päivän perästä ole syntymaallansa nähty. Tämän Tapion esiisät olit vanhasta Wenäjästä syntyjin. Hänki oli pitäjän herroille, erinomattain kinkerireisuilla, ollut tyly, komppasananen, ylävä ja näsäviisas. Sentähden vihasit häntä herrat; ja ehkä lähellä kirkkoa olis ollut maa, joka pappilaksi olisi soveliain ollut, niin laitettiin kuitenkin papin asuttavaksi Tapion maa, josta on lähes kaksi neljännestä kirkolle. Kirkonrakennus aljettiin edellä mainittuna vuonna ja päällesoisoi neljä ajastaikaa Seurakunnan köyhyyden tähden. Se seisoo kauniilla niemellä Kiantajärven rannalla. Gustavuksen sodan aikona, koska pappi ensimmäisiä toimituksia piti täsä Herran huoneesa, tapahtui että muuan unteruppseeriki värvinkiasioisa Jumalanpalmeluksen aikana löydyttäysi seuronensa kirkon ovella ja asetti siihen vahdit, ett'ei yksikään sieltä ulospäässyt. Tämä hämmästytti aivan paljon sinne kokouneita sanankuulioita, mutta pappi ei siitä pahon hämmästynyt. Hän toimitti toimitettavansa ja vasta Jumalanpalveluksesta päästyä alkoi hän nuhdella tätä ilkivaltasta työtä, joka myös saatto unteruppseerille kirkonrangastuksen ja sakon.
Ehkä tämä Herran huonet on kaikkein soveliammalla paikalla
Seurakunnan sisällä, niin on sinne kuitenki usiammilla aina kuudenki peninkuorman matka kuljettavana. Tämä matka on sekä kesän että talven hankale ja kankera. Kesällä on pitkät, aavat järvet matkattavana, joisa rajuavat myrskyt välimiten estävät kaiken kulun. Talvella taas on matka synkkäin erämaitten läpi, joisa ei useenkaan, keskitalvella, erinomattain lumisina talvina ole muuta ihmisten kulkutietä kuin sillon ja tällön joku suksilatu. Sentähden ne etäisimmät tuskin pari kertaa vuodesa kulkevat kirkolle; toiset taas käyvät neljä ja viisi kertaa vuodesa, seuraavina juhlapäivinä, nimittäin Jouluna, Pääsiäissä, Juhannussa, Perttulina, Mikkelinä ja
jonaki Rukouspäivänä. Mutta silloin kokouvat Seurakunnan jäsenet niin kosolta, ett' ei kirkko ole kyllä avara niitä suojohinsa ottamaan. Usein on niinä juhlapäivinä neljäki sataa henkiä ehtoollispöydällä.
Wanhan tavallisuuden jälkeen pidetään vielä kinkeriä, kerta keväillä, toinen syksyllä, ympäri Seurakunnan. Niisä tapahtuvat samat toimitukset, kuin muinosinakin aikoina, paitti sitä ett' ei luvun koetukset enää ole niin rajuset ja sotaset. Harvat ovat poisa näistä kintereistä, ja nämät ovat vieläki ne ainoat tilaisuudet, joissa vanha väki, jotka eivät enää kykene Herran huoneeseen, saavat papin suusta kuulla Jumalan sanaa.
Wäen laskusta ja taloin luvusta ja ladusta; ynnä pellon ja halmetten viljelemisestä.
Ensimmäisen opettajan tänne tultaissa ei väen lasku varsin tavoittanut tuhattakaan henkiä; nyt on täällä neljällä tuhatta asujanta, jotka majailevat 150:sä verotaloudesa ja 100:dasa torppa- ja mäkikotuksesa. Nämät taloudet ovat sinne ja tänne ikääskun piristellyt, ympäri laveita erämaita. Suurin osa on kuitenki, niinkuin jo mainittiin, Kiannan ja Wuokin avarain vesien rannoilla. Ensimmäiset tänne talottuneet asujamet elättelit ittiänsä halmetten viljelemisellä, mettä- ja vedenviljalla; siitä syystä ei he juuri, asuntopaikkoja valitessa, kattoneet peltomaan hyvyyttä ja hallan estämistä, jonka tähden vanhat asunmajat havataan alhaisilla maisemilla, usein soiden rannoilla, aina kuitenki vetten partaalla tehdyiksi, että kalavesi aina oli saapuvilla. Kuin nyt talouden sioja valittaisa pääasia, nimittäin peltomaan hyvyys ja hallan turmio unhotettiin, niin on monen täytynyt jättää esiisänsä majapaikat autioksi ja muuttauta korkiammille vaaroille, joisa heillä oli sekä soveliampi maa pellon viljelemiseen, että he ynnä siellä olit paremmin rauhotetut hallan
vahingosta. Mutta se onnetoin esiisiltä peritty tapa, että maan halmetmaitten viljelemisellä pyytää elatusta hankkia, jotka ei kuitenkan enää, soveliasten maitten puuttuisi, voi elättää; on saattanut sen suuren vahingon, että peltotyö on laimilyöty. Sentähden tavataan täällä vähän peltoja ja nekin vähät usein niukasti lannottuina, viattomina, kivisinä ja muuten pahoin viljellyinä, ja suuri syy siihen nälkään, joka meitä jo vuosikymmeniä on surkiasti rasittanut, tulee epäilemättä halmetmaitten mitättömästä viljelemisestä hallasilla ja epäpätösillä maisemilla, ja pellon laimilyödystä viljelemisestä ja siis huonosta lannottamisesta.
Se on imeheltävätä, kuinka esiisäin tavat muutamisa asioisa heidän jälkeeneläjittensä tykönä ovat syvästi juurtuneet. Muinosina aikoina oli halmettyö suuresti viljavata. Puisevia ja hedelmällisiä korkioita vaaroja ja kunnaita löytyi yli kaiken; jotka halmeeksi olivat aivan soveliaat. Ne maksoit monikertasesti viljeliänsä vaivat; usein antoi kapan kylvö 20 kappaa. Ei ihmet siis, jos sillon halmeita viljeltiin! Nyt on asia kokonansa toisin. Ei yhtään vaaraa löydy, joka ei jo monikertasesti ole halmehittu ja poltettu. Se ei enää voi hyvää hedelmätä kantaa; kuitenki haparoivat ihmisraukat sydänmaitten ympäri niitä etsiesä ja hankkiesa, josa turhasa työsä satoja kesäsiä päiviä tuhlataan. Jos kaikki tämä aika ja työ akkunan alla ja pellolla käytettäskin, niin kasvaisi vuoden vilja, Herralta siunattuna, meidänki maillamme ja survoton leipä kaunistaisi meidänki pöytämme, josta perheen isä väkinensä nautittis toivotun ja tarveellisen ravinnon.
Ruis ja ohra ovat ne touvon laadut, joita täällä viljellään, mutta jotka halla useen turmelee. Potakka, se siunattu touko joka täälläki paraiten kestää hallaa, on vielä harvoilta niin viljelty ja rakastettu kuin se itte työsä ansaittis. Ensimmäiset potakan siemenet lähetti tänne Suomen Huoneenhallituksen Seura, neljättäkymmentä muotia sitten
Seurakunnan senaikaselle Opettajalle, joka niistä, ensikerran kylvettyä, sai runsaan hedelmän ja jakoi aluksi siementä talonpojille, jotka kuitenkaan ei niistä ensimmälta paljon pitäneet. Täsä johtuu mieleeni meidän vanhan kirkkoväärtimme lause niistä. Hän oli kerran sattunut tulemaan pappilaan puolisten aikona ja sisälle astuttuaan havatti hän papin murkinoivan rasvasa paistetuita potakoita. Pappi lausui hänelle: "Tulkaapas Tekin, kirkkoväärti, maistelemaan tätä meidän uutta toukoamme." Kirkkoväärti tulikin, mutta jo ensi potaatin syötyä sanoa hotasi hän: "Noh! syöpi tuota rasvan kanssa vaikka tervanahturin." — Tosin sivistämättömän Pohjanmaan urohon lausunto! Jo nykysinä aikoina tuntisi tämänki maan asujat potaatein hyödyn ja maullisuuden. Itte se kirkkoväärti, josta äskeen mainittimma, on jo monta kertaa syönyt niitä makiaan suuhunsa. Mutta siitä on pahin että harvat voivat säilyttää siemeniä yli taimen, jonka tähden tämä touvon laatu ei pääse täällä oikeen eistämään. Kauroja täällä ei ensinkään viljelläkkään.
Satuja.
1. Joki ja Lähde.
Joki ja Lähde riitautuvat välillään, kumpi olisi toista parempi ja etevämpi. "Kun toki kehtoatki minun rinnalleni pistäytä, sano joki, etkö näe kuinka paljoa parempi minä olenki! Julkisesti kuljen minä ihanien kukkanurmim halki, rannoillani elää kauneita kyliä ja rikkaita kaupunkeja, yhtäläiseen kulkee laivoja tavaroinensa pinnallani, kaikki elävät kiittävät minua ja minäpä se voimassa pidän itse merenki, sillä ilman taitaisi pian kuivaa. Sinä sitä vaston juokset
maan alla piilossa ja tuskin kehtaat silmäsi muille näyttää." Tästä herjaamisesta lähde niin häpesi, ettei enää näyttänyt ollenkan silmiään, vaan asti aina maan alla. Waan siitäpä kuivi pian koko jokiki, jolla oli lähteestä ensialkunsa. Niin katumuksekseen pian havatsi väärin tehneensä lähdettä soimatessa.
Elä suulla suurentele, ellet kunnossa kyenne.
2. Waimo, Miehensä ja Kuolema.
"Woi jos saisin minä sinun siastasi kuolla," sano vaimo sairaalle miehellensä, jota jo kaikiltai kuolevaksi katsottiin. Kuolema jo porstuassa ollen kuuli vaimon sanat ja astu sisälle. "Kuka te oletta?" kysy vaimo. "Olenpa kuolema, vastasi toinen, oletko nyt valmis seuraamaan?" Waimopa tuskastu ja lausu osottaen miehensä vuoteelle: "tuolla hän makaa, jota etsittä."
Ei suuret sanat suuta halkase.
taikka
Ei lupa taloa hävitä.
Suomen kansan, Arvutuksia.
1. Ori juoksi, ohjat notku, tie vieri, reki ratisi.
2. Lautta lammissa; ei vety, eikä märkäne.
3. Kiuskaa, kauskaa, tihiässa viitassa.
4. Ori orpo virpoharja, seisovi pyhällä maalla, vihityllä vinkautti, kuuluvi kumia ääni pyhän pellon pientarelta.
5. Musta härkä tervaselkä, pyhän pellon pyörtänöllä.
Osviittoja. 1. Rukki (keträäminen). 2. Kieli. 3. Keritsimet. 4. Kellotapuli. 5. Kirkko.
Suomen kansan Sanalaskuja.
1. Parempi laiha sovinko, kun lihavai voitto.
Riitahalusilla tarkon mieleen pantava sanalasku.
2. Parempi pahaki leikki, hyveäki tappeloa.
Kyllä tosi sanalasku ja ehkä toisinaan niiltä muistettava, jotka itset, nuoruusikänsä ylimentyä, eivät suatsisi nuorten konsa keskenänsä leikittelevän eli muuten ilosina elämän.
3. Saa tyhjän tekemättäi, valehen vatomattai.
Toiset sanovat: S. t. t., vannomattaki valehen ja kummalla tavalla tahansa osottavat sanat, ei tarvitsevan aikaansa tyhjissä yritteissä kuluttaa.
Ota virpi viittä syltä, Ora seitsentä satoa; Kaiota kalaset karjat, Nosta ruotoset rominat, Eillä haukiset hajota, Käännä maimat maata vasten, Minun siulan siirtämille, Kiveksen kupestamille.
2. Ahti, ainonen kuningas, Ween hauan hallitsia!
Ota kilpesi koria, Kultalumpi luikahuta, Jolla karkotat kaloja, Luoksi koukkuni kokoat.
Anna mulle ahvenia, Pistä piikkiselkiäsi, Alta mustien murien, Alta aavojen syvien.
Tuulelle.
Kuinka sillon lauletahan,
Ja kuten kujerretahan, Kun ei vie vesi venettä,
Aalto laivoa ajele,
Tuuli purtta tuuvittele?
Noin sillon saneltanehe:
Nouse tuuli tuulemahan, Ilman ranta riehkimähän, Anna airoille apua, Huoparille huovitusta.
Kun lähin vesille raukka
Wenehellä pikkusella,
Wäellä vähäpäöllä;
Aivan on airot pikkaraiset,
Soutajat vähäväkiset, Perimiehet pienenlaiset.
Puhu tuuli purteheni, Ahava venoseheni!
Kukliksi meno vesillä, Lumpehiksi lainehilla, Jotta juosta puisen purren, Mennä mäntysen venehen; Juosta purren puittomia, Kiiteä kivittömiä.
Sateelle. Mene pilmi Pietulahan, Siellä vettä tarvitahan;
Siell' on kaivot kuivillahan, Siellä käymättä oluet, Wielä lapset ristimättä, Kastamatta kaikki tyyni; Kaikki kaivot kuivanehet, Lähtehet läkähtynehet.
Jälkimaine. Tämmöisiä sanoja oli ennen pian kaikissa tarpeissa ja luultiin niitä sillon väkeviksi välitteiksi, kaikenlaisia vaikuttamaan. Ken niitä enemmän tiesi ja niiden ohessa älysi muutenki mahtavan tavoin käyttäytä, häntä pidettiin suurena tietäjänä. Paljo vähennyt on nykyään sanoilta arvonsa, vaikk' ei kuitenkan niin, ettei vieläki joita kuita yksinkertasia löytyisi, jotka luulevat niillä jotai erityistä voimaa olevan. Tosi onki, että muutamat sanat, mieltä kovasti liikuttamalla,
voivat jotai vaikuttaa, vaan tyhjään luulevat sillonki, minkä voiman itsissä sanoissa olevan. Muulla säikähyttämällä, kauhistuttamalla eli mielen levottamalla, toivon lisäämällä on ainaki sama vaikutus, sanat ja muut ohelliset käytökset olkaan mitkä tahansa. Peräti älytöntä on, luulla tuulen, sateen, kalojen, lintuin, oravain ja muiden semmoisten sanoista miksikän muuttuvan.
Toholahden Markkinoista.
Saanenko sanoa vielä,
Mit' on mielessä' minulla
Elämästä entisestä,
Niinkun nytki nykysestä.
Ennen elivät paremmin 5
Leivän kanssa kaikki tyyni,
Rahat talossa takana,
Eikä velkoa verosta,
Ruunumiesten ruopotella.
Talo kuki kunnollansa 10
Ite piti Perjakkansa,
Eikä sarvia sahattu;
Oli vapana vasara
Talon kaikista kaluista.
Nyt jo vieään vinkuvatki, 15
Mit' on ihan irtanaista
Talon seinien sisällä;
Haetaanpa halmehetki
Syänmailta synkiöiltä;
Kaikki kaupaksi menemat. 20
Kun jo kaikki on katottu,
Eikä löyvy enempätä
Talon tasotun kohalla,
Kohta Kuopioon kovasti
Herra alkapi ajella, 25
Kanselian kartanolle.
Siellä sileetä tekepi,
Siellä' poies siirtelepi
Ihan entiset asujat
Talon permannon periltä, 30
Linnun lailla lentämähän.
Tämän kovan kurituksen,
Armottoman ahistuksen,
Ehkä ite ansahtimma
Pahan palkaksi elämän. 35
Siitä minun mielestäni
Tämä köyhyys on kytennyt,
Että Pieksämään pitäästä
Markkinat majoille niille
Toholahtehen tulivat, 40
Sihen salmen sillan päähän, Liian kirkkoa likelle.
Nyt ne isännät illolla
Kaikki kantavat rahansa
Rouarille, kauppialle, 45
Weron jättävät velaksi.
Samat markkinat sanotut
Tuli varsin vastuksiksi,
Kyllä köyhyyen lisäksi,
Joka syksy syntiseksi 50
Kaiken pahuuen pajaksi.
Sihen siirtyvät kokohon
Häjynilkiset ilolla,
Häjy joukko juoninensa
Pitämään pitoja niitä, 55
Mainitulta markkinoita.
Oispa rengit rikkahammat, Kun ei oisi vllenkana
Näitä maamme markkinoita
Rautalampihin rakettu. 60
Sinne palkkansa panevat,
Ansionsa ammuntamat,
Antavat rahansa raukat,
Puotipojalle jakavat,
Kaikenlaisesta kalusta, 65
Mielestäni miltömästa.
Toistepa tulepi tarves.
Että pitäisi pihissä
Olla sillänsä setelit,
Waan on kaikki kauppialla 70
Ennen aion annettuna;
Ei ou miehellä mitänä,
Jolla ostaisi jotaki,
Waikka varsin tarpehessa.
Wielä piivistä pitäisi 75
Sana muutama sanoa,
Halki haastella asia, Kuin ma olen kuulla saanut.
Seisoin kerran seinuksella,
Ahtahan solan sisässä, 80
Ihan ilman äänetönnä;
Kuulin kummia sanoja.
Sanoi tyttö toisellensa:
"Onko sulla ollenkana, Koottua kopeikkoana, 85
Jolla ostaisit jotai,
Makeisia markkinoilla, Eli huivin huonommanki, Sormuksen eli solenki?"
Toinen vastasi vakasti, 90
Hiljaksensa hienommasti:
"Ei ou tenkoa tinaista;
Enkä minä millonkana
Makeisia markkinoilta
Ostanna omin rahoini, 95
Ehk' oun syönynnä enemmin, Kun ne ostajat ovatkan; Raahtiko rahalla syöä, Mahamääreä mäkätä!"
Kysy siitä toinen tyttö: 100
"Kuka ihan ilmasesta
Sinun niin nyt syöttelepi, Läpi täyttäpi mahasi?"
Sano raaski tyttö toinen:
"Kun et virka, kultaseni, 105
Siitä millonkan mitänä,
Niin mä sanelen sinulle:
Sinne jättäiten jälelle,
Seison puoin seinuksella,
Wasta pistäiten pimeellä 110
Kauppamiehen kainalohon,
Olen yötä sen ohessa,
Eihän pitäne pahana."
Wasta tuosta toinen oppi,
Heti sanopi samassa: 115
"Ihan ensimarkkinoilla
Minä seurelen sinua;
Jäähäänpä yöksi yhessa
Puoliherran puolisoiksi,
Otetaanpa oivalailla 120
Tavaroita taltehemme,
Makeisia, huivisia,
Waikka vielä puumulia."
Sitte loppu se tarina;
Alkovat niin astuksella 125
Poies siitä seinukselta,
Minust' ei tiennehet mitänä, Waikka kuuntelin kovasti
Piikajen neuopiettä.
Jälkimaine Juhana Ihalaisen tekemä runo. Niin Toholahdessa, kun muuallaki meidän maassa, on valitettavasti paljo tapaturmioa markkinoista syntynyt. Sentähdenpä esivalta niitä onki hävittänyt
