Tuberculosis lymphadenitis, a diagnostic problem in areas of high prevalence of HIV and tuberculosis

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Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis

BACKGROUND: As well as being inducible by haem, haemoxygenase -1 (HO-1) is also induced by interleukin-10 and an anti-inflammatory prostaglandin, 15d PGJ(2), the carbon monoxide thus produced mediating the anti-inflammatory effects of these molecules. The cellular distribution of HO-1, by immunohistochemistry, in brain, lung and liver in fatal falciparum malaria, and in sepsis, is reported. METHODS: Wax sections were stained, at a 1:1000 dilution of primary antibody, for HO-1 in tissues collected during paediatric autopsies in Blantyre, Malawi. These comprised 37 acutely ill comatose patients, 32 of whom were diagnosed clinically as cerebral malaria and the other 5 as bacterial diseases with coma. Another 3 died unexpectedly from an alert state. Other control tissues were from Australian adults. RESULTS: Apart from its presence in splenic red pulp macrophages and microhaemorrhages, staining for HO-1 was confined to intravascular monocytes and certain tissue macrophages. Of the 32 clinically diagnosed cerebral malaria cases, 11 (category A) cases had negligible histological change in the brain and absence of or scanty intravascular sequestration of parasitized erythrocytes. Of these 11 cases, eight proved at autopsy to have other pathological changes as well, and none of these eight showed HO-1 staining within the brain apart from isolated moderate staining in one case. Two of the three without another pathological diagnosis showed moderate staining of scattered monocytes in brain vessels. Six of these 11 (category A) cases exhibited strong lung staining, and the Kupffer cells of nine of them were intensely stained. Of the seven (category B) cases with no histological changes in the brain, but appreciable sequestered parasitised erythrocytes present, one was without staining, and the other six showed strongly staining, rare or scattered monocytes in cerebral vessels. All six lung sections not obscured by neutrophils showed strong staining of monocytes and alveolar macrophages, and all six available liver sections showed moderate or strong staining of Kupffer cells. Of the 14 (category C) cases, in which brains showed micro-haemorrhages and intravascular mononuclear cell accumulations, plus sequestered parasitised erythrocytes, all exhibited strong monocyte HO-1 staining in cells forming accumulations and scattered singly within cerebral blood vessels. Eleven of the available and readable 13 lung sections showed strongly staining monocytes and alveolar macrophages, and one stained moderately. All of the 14 livers had strongly stained Kupffer cells. Of five cases of comatose culture-defined bacterial infection, three showed a scattering of stained monocytes in vessels within the brain parenchyma, three had stained cells in lung sections, and all five demonstrated moderately or strongly staining Kupffer cells. Brain sections from all three African controls, lung sections from two of them, and liver from one, showed no staining for HO-1, and other control lung and liver sections showed few, palely stained cells only. Australian-origin adult brains exhibited no staining, whether the patients had died from coronary artery disease or from non-infectious, non-cerebral conditions CONCLUSIONS: Clinically diagnosed 'cerebral malaria' in children includes some cases in whom malaria is not the only diagnosis with the hindsight afforded by autopsy. In these patients there is widespread systemic inflammation, judged by HO-1 induction, at the time of death, but minimal intracerebral inflammation. In other cases with no pathological diagnosis except malaria, there is evidence of widespread inflammatory responses both in the brain and in other major organs. The relative contributions of intracerebral and systemic host inflammatory responses in the pathogenesis of coma and death in malaria deserve further investigation

Causes of cervical lymphadenopathy at Kamuzu Central Hospital

AimDescription of pathologic causes of cervical lymphadenopathy at Kamuzu Central Hospital.IntroductionThe evaluation of cervical lymphadenopathy is a common diagnostic challenge facing clinicians. Previously at Kamuzu Central Hospital (KCH) tuberculosis (TB) was reported to be the most common cause of cervical lymphadenopathy However, no recent study has assessed this common diagnostic challenge in Malawi, particularly since the beginning of the HIV epidemic and the subsequent scale-up of antiretroviral therapy.MethodsWe conducted a cross-sectional study of all cervical lymph node specimens from the KCH pathology laboratory between 1 July 2011 and 28 February 2013 and describe patient age, gender, and pathologic diagnoses.ResultsOur search of the KCH pathology database yielded 179 cases. Of these, 143 (77%) were histologic specimens (open biopsy or core needle samples) while 34 (23%) were cytology specimens. The age range was from 0 to 76 years with a mean of 30 (SD: 19). In adults, the most common diagnosis was malignancy (n=41, 35%), while in children 15 cases each of malignancy and benign masses were diagnosed. Only 6 cases (5%) of TB were diagnosed in adults, and 4 cases (6%) of TB were diagnosed in children.ConclusionOur study shows more malignancy and much less TB than a prior study of cervical lymphadenopathy at KCH. With the successful initiaion of the KCH Pathology Laboratory in 2011, we recommend biopsy or FNA early in the workup of cervical lymphadenopathy to prevent long delays in diagnosis and treatment of curable cancers

Tissue distribution of migration inhibitory factor and inducible nitric oxide synthase in falciparum malaria and sepsis in African children

BACKGROUND: The inflammatory nature of falciparum malaria has been acknowledged since increased circulating levels of tumour necrosis factor (TNF) were first measured, but precisely where the mediators downstream from this prototype inflammatory mediator are generated has not been investigated. Here we report on the cellular distribution, by immunohistochemistry, of migration inhibitory factor (MIF) and inducible nitric oxide synthase (iNOS) in this disease, and in sepsis. METHODS: We stained for MIF and iNOS in tissues collected during 44 paediatric autopsies in Blantyre, Malawi. These comprised 42 acutely ill comatose patients, 32 of whom were diagnosed clinically as cerebral malaria and the other 10 as non-malarial diseases. Another 2 were non-malarial, non-comatose deaths. Other control tissues were from Australian adults. RESULTS: Of the 32 clinically diagnosed cerebral malaria cases, 11 had negligible histological change in the brain, and no or scanty intravascular sequestration of parasitised erythrocytes, another 7 had no histological changes in the brain, but sequestered parasitised erythrocytes were present (usually dense), and the remaining 14 brains showed micro-haemorrhages and intravascular mononuclear cell accumulations, plus sequestered parasitised erythrocytes. The vascular walls of the latter group stained most strongly for iNOS. Vascular wall iNOS staining was usually of low intensity in the second group (7 brains) and was virtually absent from the cerebral vascular walls of 8 of the 10 comatose patients without malaria, and also from control brains. The chest wall was chosen as a typical non-cerebral site encompassing a range of tissues of interest. Here pronounced iNOS staining in vascular wall and skeletal muscle was present in some 50% of the children in all groups, including septic meningitis, irrespective of the degree of staining in cerebral vascular walls. Parasites or malarial pigment were rare to absent in all chest wall sections. While MIF was common in chest wall vessels, usually in association with iNOS, it was absent in brain vessels. CONCLUSIONS: These results agree with the view that clinically diagnosed cerebral malaria in African children is a collection of overlapping syndromes acting through different organ systems, with several mechanisms, not necessarily associated with cerebral vascular inflammation and damage, combining to cause death

Human papillomavirus in head and neck squamous cell carcinoma: A descriptive study of histologically confirmed cases at Kamuzu Central Hospital in Lilongwe, Malawi

Background: Head and neck squamous cell carcinoma (HNSCC) is common in sub-Saharan Africa, but the aetiologic contribution of human papillomavirus (HPV) is not well established.Methods: We assessed HNSCC cases for HPV using p16 immunohistochemistry (IHC) in Malawi. Associations between p16 IHC and tumour site, behavioural risk factors, demographic characteristics, and HIV status were examined.Results: From 2010 to 2014, 77 HNSCC cases were identified. Mean age was 52 years, 50 cases (65%) were male, and 48 (62%) were in the oropharynx (OP) or oral cavity (OC). HIV status was known for 35 patients (45%), with 5 (14%) HIV-infected. Substance use was known for 40 patients (52%), with 38% reporting any tobacco and 31% any alcohol. Forty-two cases (55%) had adequate tissue for p16 IHC, of which seven (17%) were positive, including 22% of OP/OC tumours.Conclusions: Despite high cervical cancer burden, HPV-associated HNSCC is not very common in Malaw

Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis

Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens. Mutational signature analysis revealed common signatures associated with aging, cytidine deaminase activity (APOBEC), and a third signature of unknown origin, but signatures of inhaled tobacco use, aflatoxin and mismatch repair were notably absent. Based on RNA expression analysis, ESCC could be divided into 3 distinct subtypes, which were distinguished by their expression of cell cycle and neural transcripts. This study demonstrates discrete subtypes of ESCC in SSA, and suggests that the endemic nature of this disease reflects exposure to a carcinogen other than tobacco and oncogenic viruses

STD/HIV control in Malawi and the search for affordable and effective urethritis therapy: a first field evaluation.

OBJECTIVES--To evaluate gonococcal (GU) and nongonococcal urethritis (NGU), chlamydia antigen, and serostatus for syphilis and human immunodeficiency virus (HIV) among males attending a Malawian STD clinic with complaints of urethral discharge and/or dysuria. To collect demographic and behavioural data and to determine the effectiveness of five treatments for urethritis. METHODS--Urethritis was diagnosed using microscopy and culture for Neisseria gonorrhoeae. Sera were screened with rapid plasma reagin (RPR) and if reactive, with microhaemagglutination for Treponema pallidum (MHA-TP). HIV antibodies and chlamydia antigen were detected using enzyme immunoassay. Patients were randomised for treatment, cure was assessed 8-10 days later. RESULTS--At enrolment, GU was diagnosed in 415 (80.3%) and NGU in 59 (11.2%) of 517 males. Chlamydia antigen was found in 26 (5.2%) of 497 specimens tested. Syphilis seropositivity rate (RPR and MHA-TP reactive) was 10.7%. Overall HIV seroprevalence was 44.2%; 71.7% of men with reactive syphilis serology were HIV(+) compared with 40.9% of syphilis seronegatives (OR: 3.6, p < 0.001). Trimethoprim 320 mg/sulphamethoxazole 1600 mg by mouth for 2 days (TMPSMX), or the combination of amoxicillin 3 gm, probenicid 1 gm, and clavulanate 125 mg by mouth once (APC), failed to cure gonorrhoea effectively. Amoxicillin 3 gm, probenicid 1 gm, and clavulanate 125 mg, by mouth once with doxycycline 100 mg BID for 7 days (APC-D), gentamicin 240 mg IM once (GENT), ciprofloxacin 250 mg by mouth once (CIPRO) cured 92.9% to 95% of gonorrhoea. APC-D treatment did not generate less NGU at follow-up. HIV serostatus did not affect cure of urethritis. CONCLUSION--All patients presenting with urethritis should be treated syndromically using a simple algorithm and screened for syphilis seroreactivity for appropriate treatment and counselling

Causes of cervical lymphadenopathy at Kamuzu Central Hospital

Aim: Description of pathologic causes of cervical lymphadenopathy at Kamuzu Central Hospital. Introduction: The evaluation of cervical lymphadenopathy is a common diagnostic challenge facing clinicians. Previously at Kamuzu Central Hospital (KCH) tuberculosis (TB) was reported to be the most common cause of cervical lymphadenopathy However, no recent study has assessed this common diagnostic challenge in Malawi, particularly since the beginning of the HIV epidemic and the subsequent scale-up of antiretroviral therapy. Methods: We conducted a cross-sectional study of all cervical lymph node specimens from the KCH pathology laboratory between 1 July 2011 and 28 February 2013 and describe patient age, gender, and pathologic diagnoses. Results: Our search of the KCH pathology database yielded 179 cases. Of these, 143 (77%) were histologic specimens (open biopsy or core needle samples) while 34 (23%) were cytology specimens. The age range was from 0 to 76 years with a mean of 30 (SD: 19). In adults, the most common diagnosis was malignancy (n=41, 35%), while in children 15 cases each of malignancy and benign masses were diagnosed. Only 6 cases (5%) of TB were diagnosed in adults, and 4 cases (6%) of TB were diagnosed in children. Conclusion: Our study shows more malignancy and much less TB than a prior study of cervical lymphadenopathy at KCH. With the successful initiaion of the KCH Pathology Laboratory in 2011, we recommend biopsy or FNA early in the workup of cervical lymphadenopathy to prevent long delays in diagnosis and treatment of curable cancers

Early Experience after Developing a Pathology Laboratory in Malawi, with Emphasis on Cancer Diagnoses

Abstract Background: Despite increasing cancer burden in Malawi, pathology services are limited. We describe operations during the first 20 months of a new pathology laboratory in Lilongwe, with emphasis on cancer diagnoses

Early Experience after Developing a Pathology Laboratory in Malawi, with Emphasis on Cancer Diagnoses

BackgroundDespite increasing cancer burden in Malawi, pathology services are limited. We describe operations during the first 20 months of a new pathology laboratory in Lilongwe, with emphasis on cancer diagnoses.Methods and FindingsWe performed a cross-sectional study of specimens from the Kamuzu Central Hospital pathology laboratory between July 1, 2011 and February 28, 2013. Patient and specimen characteristics, and final diagnoses are summarized. Diagnoses were categorized as malignant, premalignant, infectious, other pathology, normal or benign, or nondiagnostic. Patient characteristics associated with premalignancy and malignancy were assessed using logistic regression. Of 2772 specimens, 2758 (99%) with a recorded final diagnosis were included, drawn from 2639 unique patients. Mean age was 38 years and 63% were female. Of those with documented HIV status, 51% had unknown status, and 36% with known status were infected. Histologic specimens comprised 91% of cases, and cytologic specimens 9%. Malignant diagnoses were most common overall (n = 861, 31%). Among cancers, cervical cancer was most common (n = 117, 14%), followed by lymphoma (n = 91, 11%), esophageal cancer (n = 86, 10%), sarcoma excluding Kaposi sarcoma (n = 75, 9%), and breast cancer (n = 61, 7%). HIV status was known for 95 (11%) of malignancies, with HIV prevalence ranging from 9% for breast cancer to 81% for cervical cancer. Increasing age was consistently associated with malignancy [bivariable odds ratio 1.24 per decade increase (95% CI 1.19–1.29) among 2685 patients with known age; multivariable odds ratio 1.33 per decade increase (95% CI 1.14–1.56) among 317 patients with known age, gender, and HIV status], while HIV infection and gender were not.ConclusionsDespite selection and referral bias inherent in these data, a new pathology laboratory in Lilongwe has created a robust platform for cancer care and research. Strategies to effectively capture clinical information for pathologically confirmed cancers can allow these data to complement population-based registration