Issue 10 Volume 2
Peer reviewed article
This is a case of a 32-year old man with HIV infection and candida oesophagitis. Systemic candidiasis is one of the common presenting features in late stage HIV infection in Myanmar and is considered pathognomonic for AIDS in resource poor settings. Candida oesophagitis causes epigastric pain and tends to occur concomitantly with oropha- ryngeal candidiasis, yet epigastric pain is also a leading symptom of peptic ulcers, which are common in Myanmar. Therefore, it can easily mislead doctors to diagnose a peptic ulcer and treat accordingly. In Myanmar private health care physicians and traditional healers are initial points of contact for the majority of the population seeking health care. If private general practitioners misdiagnose, it will delay diagnosis of AIDS, resulting in further HIV transmission to others and subsequent complications for the presenting patient. This is pertinent as Myanmar has the second highest HIV prevalence in Southeast Asia, hence this case elucidates how important it is for a clinician to have a high index of suspicion for HIV infection in a patient who presents with epigastric pain, chronic fever, chronic diarrhea and weight loss.
A 31-year-old man presented with a five week history of fever, four week history of epigastric pain, semi-solid bowel movements, dysphagia, weight loss and a two week history of mild headache. He described the character of his epigastric pain as burning, which was not exacerbated or alleviated by meals and did not radiate to the back. The site was constant, localized and he experienced insomnia due to continuous burning pain although the pain did not improve or worsen at any time during the day or night. During this time his initial point of contact with health services was a traditional healer who administered a remedy that did not relieve his symptoms. It was unknown by the patient what the contents of the remedy were. This patient had no history of regular medication before his current illness. He had sex with female sex workers, at times without condoms although his last contact was 5 years ago. This is because he developed purulent discharge with dysuria following his last contact, which was relieved by a general practitioner prescribing medication. The patient was unable to identify the medication or name his previous infection. He did not provide any previous history pertinent to peptic ulcer and gastro-oesophageal reflux disease.
Upon physical examination he appeared pale and emaciated. The body temperature was 37.8 degrees Celsius. His other vital signs such as blood pressure and respiratory rate were within normal range. His palate and pharynx showed white patches with erythema along the rims. Examination of heart and lungs revealed no abnormalities. There were no obvious signs of dehydration. The initial differential diagnosis list included opportunistic infection due to HIV, peptic ulcer in addition to HIV infection, malaria as he came from an endemic region and tuberculosis as this is the most common opportunistic infection in the population. Upon reflection it may have been prudent to include neoplasia in this list given the clinical signs and symptoms.
A complete blood count revealed a hemoglobin of 8.6 gm/dl, white blood cell count of 4,810/ mm3 with 79% neutrophils, 7.7% lymphocytes, 0.2% eosinophil, 0.06% basophils and 8.4% monocytes. He had a platelet count of 688,000/ mm3 and an ESR of 95 mm after the first hour. His blood glucose and electrolytes levels were within normal limits. Rapid diagnostic test for malaria was negative. Serological tests for hepatitis B and C were negative. However, his HIV rapid diagnostic test results were positive. The CD4 count was 66/mm3. The stools were examined for evidence of parasitic infection and were found to be negative.
He then underwent an upper gastrointestinal endoscopy which showed candidiasis at middle and lower end of the esophagus with no varicose vein or evidence of reflux. However, the stomach had mild mucosal congestion and edema at the pyloric antrum with no growth and ulceration. The diagnosis was acquired immunodeficiency syndrome (AIDS) with oesophageal candidiasis.
Oral fluconazole was initiated at the dose of 200mg daily for 14 days. Then for fever and diarrhea, he was given ciprofloxacin 500mg twice a day for 5 days and he also received co-trimoxazole as a primary prophylaxis of Pneumocystic jiroveci pneumonia (PCP) and toxoplasmosis and ranitidine 300mg daily for mild gastritis. He was also suggested to take a nutritious diet and vitamins. He showed significant improvement of his burning pain. In addition, loose motion and fever subsided within a week.
There were strong indications for antiretroviral therapy (ART) so other laboratory and radiological investigations were done as a part of preparation for ART. Sputum microscopy for acid fast bacilli (AFB) were negative and chest radiography revealed no abnormalities. Serological testing for syphilis was non-reactive. Serum alanine transaminase (ALT) was 22 U/L.
He started to take the first line regimen of ART after two weeks of the initial empirical antibiotic treatment with the patient’s improvement. The first line regimen includes stavudine (d4T), samivudine (3TC) and nevirapine (NVP). There was no skin rash or liver toxicity during the first two weeks of lead-in dose so the NVP dose was increased from 200mg once a day to 200mg twice a day.
One week after starting full dose of the ART, he complained of high fever, abdominal pain and loose motion again. However, he had no jaundice or skin rash. There was a high index of suspicion of Mycobacterium Avian Complex (MAC) immune reconstitution disease, hence some indirect indicators for MAC infection were used. Direct MAC diagnostic facilities were not available. On stool analysis, AFB and pus cells were seen.
Serum alkaline phosphatase (ALP) was 544 units per liter. Ultrasound abdomen showed enlarged para-aortic lymph nodes and mild hepato-splenomegaly. Therefore, he was treated as MAC by giving Azithromycin and Ethambutol. The patient improved over a 12 day course.
He completed the course of MAC treatment and has continued to take the first line ART until now. His body weight increased from 50 kilogram to 65 kilograms and the CD4 count rose to 275/ mm3 over the three years. His counselor reported that he adhered to more than 95% of his ART doses. The CD4 count has not increased beyond 300/mm3 although his HIV plasma viral load became undetectable.
Odynophagia and dysphagia are common symptoms of oesophagitis. There are many conditions causing oesophagitis: oesophagitis due to gastric acid reflux, drug-induced oesophagitis and infections. If it is not treated, they may severely compromise nutritional status of the patients and may be responsible for life threatening complications.
Oesophageal related symptoms occur in 40-50% of patients with AIDS at some point in the course of their disease. These are mainly caused
by infections. There are a variety of pathogens which may cause oesophagitis, including fungi, bacteria, viruses and protozoa. Among the causes, fungal agents especially Candida species are the most common etiology and other oesophageal disorders such as cytomegalovirus (CMV), herpes simplex virus (HSV) may coexist.  CMV infection has been reported in 10% to 28% of HIV infected patients complaining of oesophageal symptoms while HSV is diagnosed in approximately 10% of HIV infection.
Candida species may survive in food, air, floor, other surfaces and hospital environment and therefore be transmitted. Candida albicans is the major isolate found in individuals with candidiasis.  Other Candida species that cause candidiasis include Candida glabrata and Candida krusei. These Candida species are detected in 31% to 55% of healthy individuals. This is just colonization, and does not indicate active disease.
In the immunocompromised, (such as those with poor nutritional status and diabetes mellitus) taking broad spectrum antibiotics, colonization may progress to infection and produce inflammatory responses. Oropharyngeal candidiasis commonly occurs in the above mentioned conditions while oesophageal candidiasis is common in advanced immune deficiency associated with HIV infection. Although oesophageal candidiasis may occur at any stage of HIV infection, it is usually seen in patients with CD4 count of less than 200/mm3.  According to the WHO clinical staging of HIV/ AIDS, oesophageal candidiasis can be diagnosed presumptively on the basis of clinical signs or simple investigation.
Oesophageal related symptoms seen in candida oesophagitis are non-specific so it is difficult to diagnose candida as the definite cause. There is also the possibility of co-infection. Candida oesophagitis presents most commonly with dysphagia, odynophagia, and retrosternal pain but occasionally epigastric pain is the dominant symptom and fever occurs infrequently. Dysphagia and odynophagia are common symptoms not only in oesophageal candidiasis but also in CMV and HSV oesophagitis.
In this case report, the HIV infected patient presented with epigastric pain and fever. The pain is not a specific marker for oesophageal candidiasis and it can be caused by various gastrointestinal diseases such as peptic ulcer, gastroesophageal reflux and acute gastritis. As a result, it may be easy for physicians to overlook candida oesophagitis as a potential cause. However, the patient had oropharyngeal candidiasis, which should prompt the physician to consider oesophageal candidiaisis. It is also important to note that oesophageal candidiasis may be completely asymptomatic.
The treatment regimen depends on the causative organism and the drugs used for candidiasis and other viral infections are also different. If there
is coexistence of CMV or HSV with candidiasis, a combination of different drug regimens is required. Therefore, detection of definite cause is important for proper management of candida oesophagitis.
For HIV/AIDS staging and management purpose, diagnostic accuracy is important. In earlier time, Barium esophagography was a main diagnostic tool. Double contrast barium esophagography has a high sensitivity (over 80%) in detecting oesophageal lesions but radiographic abnormalities are often non-specific and endoscopy with biopsy and/or brushing is necessary to make a definite diagnosis. Endoscopy has its benefits of not only rapid and high sensitivity diagnosis but also reliable method of differentiating the various causes of oesophagitis. In a study conducted by Connolly, Forbes & Gleeson, endoscopy (without pathological support) had a sensitivity of 97.5% and a specificity of 100% compared with the sensitivity and specificity of 25% and 100% respectively for barium studies. Therefore, endoscopy has displaced radiography. In the resource limited situation, both esophagoradiography and endoscopy are not available. Therefore, clinicians in such a situation have to rely mainly on presumptive diagnosis.
Some studies have been conducted to analyse the reliability of clinical features for diagnosis. Oral thrush, either alone or in combination with oesophageal symptoms was a reliable marker of candida oesophagitis only in patients with a previous AIDS-defining event. The same study concluded that a presumptive diagnosis of candida oesophagitis on the basis of the Centers for Disease Control and Prevention (CDC) clinical criteria is a valid diagnostic method only in HIV- 1 infected patients with a previous diagnosis of full-blown AIDS. CDC clinical criteria for the diagnosis of oesophageal candidiasis are recent onset of retrosternal pain on swallowing and oral candidiasis diagnosed by the gross appearance of white patches or plaques on an erythematous base. Therefore, oropharyngeal candidiasis and oesophageal symptoms are important markers for clinical diagnosis in a situation where there are no facilities for endoscopy. However, there might be an argument that clinical diagnosis cannot exclude infectious oesophagitis caused by CMV and HSV.
In HIV infection, candidiasis is the commonest cause of oesophagitis while CMV and HSV are generally less common and they rarely occur unless CD4 count is less than 100/mm3. This means that CMV and HSV are at risk in far advanced immune deficiency. Another point is that HSV oesophagitis is frequently associated with labial or oral cavity lesions. Rationally, candidiasis should be considered as a cause of oesophagitis in HIV infected individuals with odynophagia unless it is in the state of very
low immune status. Thus, Belitsos described that if the CD4 count is appropriately low and other gastrointestinal conditions appear unlikely by history, the next diagnostic step in an HIV- infected person with odynophagia is usually an empirical trial of antifungal therapy and if it is not responsive, upper endoscopic evaluation should be done.
Asymptomatic oesophageal candidiasis is usually seen in people with significant immune suppression. It is shown in a study conducted by Zaidi & Cervia, invasive candidiasis in esophagus can be seen in 90% of patients having CD4 count less than 100/ mm3. So, severe immunocompromised HIV infected individuals are likely to get candida oesophagitis, though some will be asymptomatic.
Regarding the treatment, systemic antifungals are required for effective therapy and a 14-21 day course of either fluconazole (oral or IV) or oral itraconazole is highly effective. Other antifungals which are effective in treating oesophageal candidiasis include IV caspofungin, IV voriconazole, micafungin and anidulafungin. Although these are effective, oral or IV fluconazole remains the preferred therapy.
However, it should be noted that there is high risk of recurrence in HIV infected individuals. Fluconazole (or azole) resistance is predominantly the consequence of previous exposure to fluconazole (or azole) and it is followed by gradual emergence of non-albican Candida species, particularly Candida glabrata, as a cause of refractory mucosal candidiasis. If an individual does not improve in their candidiasis related symptoms despite fluconazole therapy, initially, it is better to consider other causes rather than resistance. It may be co-existant CMV or HSV oesophagitis or other causes of oesophagitis or incompliance of the drug. In the resource limited countries, health care providers should also be careful not to use unqualified or counterfeit fluconazole drugs which do not improve the illness.
Fluconazole refractory disease frequently develops in HIV infected individuals with very low CD4 T cell count who are not treated with ART. Zingman has shown that refractory AIDS- related mucosal candidiasis can be resolved by initiating antiretroviral therapy. ART improves immune function which fights effectively against the refractory candidiasis in synergistic action with fluconazole. Thus, ART should be initiated as quickly as possible in the case of candida oesophagitis with HIV infection. In some cases, mucosal candidiasis recurs repeatedly instead of being refractory to the treatment.
Despite the frequency of oesophageal candidiasis in HIV-infected patients, primary prophylaxis is not widely administered because the disease is not life threatening, and therapy is usually very effective. There is also some concern about drug resistance if primary prophylaxis was used extensively. However, secondary prophylaxis (with fluconazole 100mg/day or 150mg once weekly) is commonly given for patients with multiple recurrences of oropharyngeal and oesophageal candidiasis until effective ART can be instituted.
Oesophageal candidiasis is one of the common AIDS defining diseases and it can be diagnosed clinically if the patients are symptomatic and HIV has been diagnosed. It may be the first presenting symptom of AIDS in resource poor countries. Private health care providers should have a high index of suspicion and not miss the disease because it is an entry point for diagnosis of HIV infection in late stage which is necessary to initiate antiretroviral therapy as quickly as possible. Moreover, the treatment of candida oesophagitis is simple and even non-specialist medical providers can provide it at private clinics. Another important point is that if it is not relieved by fluconazole after a week, the patient should be referred to a higher level medical facility for assessment of other cause or co-existing viral oesophagitis or drug resistance. Furthermore, fluconazole is an effective drug for systemic candidiasis, there is a high risk of refractory to the drug unless ART is initiated.
In this case report, the patient was also co-infected with MAC because he was in very severe immune deficiency state (CD4 count 66/ mm3). Management of late stage of HIV infection is more difficult and complicated than that of early stage of infection. Therefore, early detection and management of HIV infection is desirable not only improves quality of life but also control to reduce complications.
Andrew Samaan & Min Zaw
Andrew Samaan obtained his Bachelor Medical Science (UNSW), ranked second in his
class and graduated with First Class Honours. He then joined the department of Anatomy
first working as a tutor then enjoying the lofty heights of associate lecturer. He was the
youngest lecturer in department history. He moved on to study medicine, a masters in tropical medicine and has been interning in his holidays at Oxford University Tropical Medicine Department since 2013.
Min Zaw is a consultant infectious diseases physician with over 30 years of clinical experience, ten of them obtained serving as an army doctor in Myanmar active war zones. He recently retired as head of infectious diseases depart- ment to become Chief Medical Officer of a 100 bed hospital in Dawei. He is looking forward to meeting and working with more Australian medical students looking for placements.
I would like to thank Dr Zaw for his time, input and guidance in the writing of this paper.
Conflict of interest
No known conflicts
1. National AIDS-STD control program DoH, Ministry of Health. Guidelines for the clinical management of HIV-AIDS in adults and adolescents. Yangon, Myanmar2004.
2. AIDSinfo Drug Database 2012 [cited 2015 Jan]. Available from: http://aidsinfo.nih. gov/drugs/116/nevirapine/0/professional – Section_5.4.
3. Parente F, Porro GB. Infectious Esophagitis: Etiology, Diagnosis, and Treatment. In: Bremner CG, DeMeester TR, Peracchia A, editors. Modern approach to benign esophageal disease. New York, USA: Quality Medical Publishing, Inc. ; 1995.
4. Zaidi SA, Cervia JS. Diagnosis and management of infectious esophagitis associated with human immunodeficiency virus infection.
J Int Assoc Physicians AIDS Care (Chic). 2002;1(2):53-62.
5. Vazquez JA, Sobel JD. Mucosal candidiasis. Infect Dis Clin North Am. 2002;16(4):793-820, v.
6. WHO. Interim WHO clinical staging of HIV/AIDS and HIV/AIDS case definitions for surveillance. Geneva, Switzerland: WHO, 2005. 7. Connolly GM, Forbes A, Gleeson
JA, Gazzard BG. Investigation of upper gastrointestinal symptoms in patients with AIDS. AIDS. 1989;3(7):453-6.
8. Antinori A, Antinori A, Ammassari A, Masetti R, De Luca A, Murri R, et al. Presumptive clinical criteria versus endoscopy in the diagnosis of Candida esophagitis at various HIV-1 disease stages. Endoscopy. 1995;27(5):371-6.
9. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-infected Asults and Adolescents. (2009).
10. Belitsos PC. Management of HIV-associated esophageal disease. AIDS Clin Care. 1995;7(3): 19-22
11. Zingman BS. Resolution of refractory AIDS-related mucosal candidiasis after initiation of fifanosine plus saquinavir. The New England journal of medicine. 1996;334(25):1674-5