Infectious DiseasesCase Presentation

18 September 2002Dr Zakeya Bukhary, Fellow,

Infectious Diseases

Dr Hail Al-Abdely, Consultant, Infectious Diseases

First Case

• A 19-year-old girl from the Eastern Province, who was completely healthy until May 2001 when started to c/o:– RIF pain and fever associated with

constipation and weight loss– The pain was colicky and slowly progressive,

moderately severe, non-radiating and not relieved by analgesics

History

History

• Fever was on and off with no diurnal variation and no night sweating or chills

• No nausea or vomiting

• No skin rash or joint pains

• Systemic review: unremarkable

History

• No Hx of TB or contact with TB patients

• No previous abdominal surgeries• No drug Hx• Lives in Dhahran

History

• At the local hospital (DHC), she was found to have ileocecal mass (5/2001)

• Colonoscopy showed ulcers of the Rt hemicolon and Bx was consistent with acute inflammation.

• Started empirically on ciprofloxacin + flagyl but without response

History

• Colonic biopsy ? Crohn’s.

• Started on oral steroids.

• Has temporary improvement and gained wt.

• Oct 2001, f/u showed an increase in the mass size clinically and confirmed by CT abdomen.

• 27 Oct 2001, laparatomy (at DHC) showed unresectable mass with intense inflammation involving the Rt. hemicolon

• Bx showed necrotizing granuloma with broad fungal hyphae. Culture was negative.

• Treated with ABLC and continued low dose steroid

• On 11 Nov 2002 referred to KFSH&RC for 2nd opinion

• Pt was clinically unwell but not toxic

• P/E:

– T 38.8ºC PR 110/min BP 120/70RR 20 Wt 49 kg Ht 158 cm

– Not in distress or jaundiced or cyanosed

– Was pale

– No LN enlargement

– Chest/heart exam unremarkable

Abd Exam

• Soft, with large, irregular, ill-defined mass extending from the RUQ to RIFand umbilical region; mildly tender and hard.

• Non-palpable liver or spleen• No ascitis• B.S. were present

InvestigationWBC 14.0 PMN 80% No bands

Lymph 20.0%Eosinophils 1.3%

Hb 92 MCV 78.8 MCH 23.4Plt 305ESR 15Urea 4.9 Cr 96Na 135 K+ 3.3ALT 50 ALP 185 Bil 4 Alb30PPD skin test –ve CXR N

CT abdomen

12 November 2001

Differential Diagnosis

D. Dx

• Deep GI mycosis

• TB

• Actinomycosis

• Crohn’s

• Lymphoma

Course

• Review of histopath slides from DHC – showed moderate chronic colitis, no cryptitis with positive granuloma and fungal hyphae

• With prominent eosinophilic infiltrate

Pathology

• Pt was spiking high grade Temp 40.0º C

• Started on Ambisome + Tazocin for possibility of perforation and superadded bacterial infection

• Pain control, NPO, TPN

• Surgical opinion confirmed that the mass was non-operable

• 14 Nov 2001– FNA and True cut Bx to get tissue for

microbiological Dx for c/s

• 17 Nov 2001– Steroids - methylprednisone 1 mg/kg/d started

Course

• 20 Nov 2001– Dx of GI mycosis confirmed by culture positive

Basidiobolus ranarum– IV itraconazole was added– Ambisome changed to Ampho B to minimize

drug induced hepatitis

Course

• f/u CT scan Abd (20/11/2001):– showed very impressive response to steroids

+ antifungal (Ampho B + short course of itraconazole) with regression of the inflammation and dilatation of the Rt. hemicolon which has emptied its content and has partly collapsed.

Course

• Clinically, pt was improving with no fever and no abd pain

• Started on oral feed

• 11 Dec 2001 discharged on ketoconazole 600 mg p.o. OD, and steroids on tapering dose

• In vitro - susceptibility test showed better inhibitory effect of ketoconazole which was started orally

CT abdomen

8/4/2002

2/9/2002

Discussion

Basidiobolomycosis

• Introduction

– Classification

– Epidemiology

– Pathogenesis & Clinical Manifestation

– Diagnosis

• Revision of invasive G.I.B.

• Rx

Zygomycetes

Mucorales(Mucormycosis)

Entomophthorales(Entomophthoramycosis)

Conidiobolus Basidiobolus

• Basidiobolus species are normal inhabitants of soil throughout the world

• They have been also isolated from the gut of amphibians and reptiles

• These fungi cause a chronic inflammatory granulomatous disease (Entomophthoramycosis)

• reported in healthy inhabitants of tropical and subtropical regions (Africa, Southeast Asia, South America)

• The mode of transmission of infection to humans remains unknown

• Inhalation, ingestion, direct inoculation and acquisition secondary to I.M. injection and insect bites have been postulated

• The disease generally manifested as subcutaneous lesions

• Visceral involvement and deep invasive infection either primary or secondary to subcutaneous disease, is rare and affects mainly immunocompromised hosts and can be fatal.

Nazir et al, Ann Trop Paediatrics 1997;17:161

• Diagnosis depends on microscopic documentation of tissue invasion and presence of typical hyphae of B. ranarum

• In contrast with mucormycosis no vascular invasion or tissue infarction or necrosis

• Lesions produced by B. ranarum are characterized by an acute and/or chronic inflammation in association with broad, irregular, erratically septate hyphae, surrounded by a distinctive eosinophilic sheath

• Culture of the fungus is the only way to identify correctly the species.

• Immunodiffusion test has been used in several patients and claims 100% specificity specificity and may have a prognostic value.

Kaufman et al, J Clin Microb 1990;28:9:1887

• The first case described of the infection was in a pt from Indonesia by Joe et al in 1956

• Approximately 300 cases (90% cutaneous) have been reported in the World Literature, mostly from Tropical Asia, Africa and South America

• A majority of cases have been in children under 10 years of age

• In 1994, a healthy 8-year-old boy reported as a case of invasive retroperitoneal infection due to B. ranarum based on histopath who did not respond to high dose Ampho B but the mass resolved completely in 6/52 in response to K1 saturated solution orally

Ann Trop Paediatrics 1997;17:161

• The 5th case was a 49-year-old lady who presented with GIB mimicking Crohn’s disease with no response to mesalamine and steroids

• Diagnosed histopathologically

• Responded clinically to oral itraconazole

Smilack et al, Gastroenterology 1997;119:250

• In 1996 B. ranarum involving the rectum was reported from Kuwait, in a 30-year-old man presented with PR-bleed and polypoid mass

• Dx confirmed by culture

• Responded to antifungals (Ampho B + ketoconazole)

Khan et al CID 1998;26:521

Am J Clin Pathol 1999;112:610

• Lyon et al conducted a case-control study to generate hypotheses about potential risk factors in the reported few cases of GIB in AZ, between 1994 to 1999.

• According to their results they considered:–Ranitidine–Smoking–Digging earth as of one’s job

• The length of residence in AZ to be associated significantly with GIB

• Some factors did not reach statistical significance, including:

–Steroids

–Use of over-the-counter drugs

–Animal contact

–Eating unwashed vegetables

• One of the cases had a Hx of PICA daily for years before the Dx of GIB

CID 2001;32:1448

• Currently, there is no means of preventing this infection or even identifying those at risk for development of this disease

• Early detection of the disease seems to be the best hope of reducing the serious morbidity and mortality associated with long-standing disease

• Based on the limited information, it appears that optional treatment of GIB combines surgical and medical methods

• Pts should undergo resection and debridement of all affected tissues; followed prolonged antifungal Rx

CID 2001;32;1448

• Clinical failures have been described in association with Ampho B

Mycopathologia 1986;95:101Am Trop Paed 1997;17:161CID 1999;28:1244

• Ketoconazole has been shown to be effective in both in vitro and in vivo studies

AAC 1984;25:413

• The best choice of antifungal agent is not clear, but itraconazole seems to have the best results

Mycopathologia 1986;95:101Am J Kidney Dis 1997;29:620Am J Clin Pathol 1999;112:610CID 1998;27:663CID 1999;28:1244CID 2001;32:1448

• In general Basidiobolus spp displays low MICs of itraconazole 0.25 g/ml, ketoconazole 0.5 g/ml

• MICs of 0.1 – 1.0 g/ml found to be inhibitory

JAC 1999;44:557

Rev Inf Dis 1987;9(Suppl 1):S15

End of First Case

Second CaseSecond Case

History

• 52Y/O American white female.– Told to have pulmonary nodules on CXR

10/9/01and subsequently on CT chest 21/9/01 in the US.

– Totally asymptomatic.– No Intervention– Moved to Saudi Arabia with her husband

(work for a Saudi bank) 11/2001

History

• Lived in: – Arkansas- childhood– California (1978-1995)– Scotland (1995-1998)– Poland (1998-2001)

History

• PMH:– Hypertension– Hyperlipidemia– S/P Hysterectomy & salpingo-opherectomy

1996 for large ovarian cyst.

Meds

• Quinapril 20mg QD

• Indapamide 1.5mg QD

• Simvastatin 40mg QD

History

• Seen in a private hospital in Riyadh– Clinical evaluation was unremarkable– PPD: negative – CT chest 17/1/02

17/1/2002

17/1/2002

17/1/2002

17/1/2002

Differential Diagnosis

What will you do next?

Intervention

• Open-Lung biopsy 6/2/02– Report

• “Caseating granuloma”.• Sent for TB culture.

Start 4 drugs anti TB (4 March 2002)High fever and diffuse skin rash (12 March 2002)

Stop anti TB Better

Course

• 20 March 2002– Further stains showed fungus– Started on fluconazole 400mg QD

– Serologies sent for:• Cryptococcal serum antigen, negative• Coccidioides ab, negative• Balstomyces ab, negative• Histoplasma ab, could not be determined

Pathology

11/6/2002

11/6/2002

• D/C fluconazole and start itraconazole 400 mg QD

• Patient did not take it.

28/8/2002

28/8/2002

Histoplasmosis

• Introduction

–Pathogenesis

–C. Fx

–Dx

–Rx

Histoplasmosis

• Histoplasma capsulatum was first described in 1905.

• It is a thermally dimorphic fungus, found in soil enriched by droppings of some birds and bats

• It can remain viable for years in the soil

Histoplasma capsulatum (filamentous phase)

Pathogenesis

• Hyphal elements of H. capsulatum, are inhaled into the lungs, where they reach the alveolar spaces and transform into yeasts forms

• Following pulmonary infection, organisms spread through lymphatics to the regional lymph nodes and hematogenously to other organs

• In immunocompetent patients resemble tuberculosis, with caseating granulomas and necrosis

• Granulomas heal with fibrosis and can calcify

• Reactive arthritis, pericarditis and erythema nodosum can present

Clinical

• The degree of exposure and immune status of the host determines the severity of the disease

• More than 95% of persons infected are asymptomatic

• Histoplasmoma: a coin-like lesion in the lungs

• In symptomatic cases:– Primary pulmonary histoplasmosis

• Mild self-limiting disease• Rarely severe with ARDS

– Chronic pulmonary histoplasmosis• Occurs in a setting of underlying

disease, e.g. COPD• Subacute recurrent pneumonia• Associated with apical fibrosis and

cavitation

• In symptomatic cases (cont.):

–Disseminated disease

• Most serious form, usually in immunodeficient patients with prolonged fever, hepatosplenomegaly, meningoencephalitis, sepsis, DIC.

Dx

• Tissue Bx stains are highly sensitive

• Immunodiffusion (more specific less

sensitive ) and complement fixation (more sensitive less specific) antibody tests assist in Dx

• Antigen detection by radioimmunoassays in serum and urine is highly sensitive and specific in disseminated disease

• In patients with AIDS who have disseminated histoplasmosis, elevated antigen levels are present in the urine in 95% of cases, and in the serum in 80%.

Therapy

• In immunocompetent patients: itraconazole is the drug of choice and it is highly effective

• Ampho B has a response rate of more than 75% in meningeal and life-threatening histoplasmosis

Dismukes et al, Am J Med 1992;93:489