HIV infection is one of the leading causes of morbidity and mortality worldwide, with most of the disease concentrated in sub-Saharan Africa. As the infection often takes hold in adults who are in the prime of their economic productivity, HIV infection has dramatically altered the economies of many countries . Regardless of its multisystem involvement, more than 20 % of patients with HIV infection remain undiagnosed. Although the overall incidence of many opportunistic infections has decreased with effective chemoprophylaxis and combination antiretroviral therapy, prompt recognition and appropriate management are imperative to decrease mortality related to these conditions . The relationship between HIV infection and typhoid has been unclear. Studies done in typhoid endemic areas have demonstrated an increased risk of typhoid and paratyphoid fever in HIV infected persons . In contrast, a study done in Tanzania showed an apparent protective effect of HIV against Salmonella as those results were explained by using trimethoprim-sulfamethoxazole prophylaxis, which could protect against typhoid fever .
The diagnosis of HIV infection remains a challenge since many patients may have an asymptomatic infection after exposure, where it takes 2 to 4 weeks from the exposure to the onset of the symptoms. In acute retroviral syndrome, symptoms like fatigue, muscle pain, skin rash, headache, sore throat and swollen lymph nodes may appear acutely. Although none of these symptoms is specific to HIV, their increased severity and prolonged duration indicate a poor prognosis . However, fever is the most common symptom of HIV infection, which present in 80–90% of patients . Chronic HIV infection can be characterized by either with or without AIDS and can progress to advanced HIV infection. In chronic HIV infection without AIDS, the predominant features include oral thrush, vaginal candidiasis, oral hairy leukoplakia, herpes zoster and peripheral neuropathy. Chronic HIV infection with AIDS is defined as a CD4 cell count < 200 cells/µL or the presence of any AIDS-defining condition regardless of the CD4 cell count. The AIDS-defining conditions include recurrent pneumonia, chronic intestinal cryptosporidiosis, Kaposi sarcoma, Burkitt lymphoma, tuberculosis, pneumocystis jirovecii pneumonia and progressive multifocal leukoencephalopathy. Advanced HIV infection is defined as a CD4 cell count < 50 cells/µL . Our patient had chronic low-grade intermittent fever with significant weight loss and anorexia for eight months, where his fever became high grade, associated with profuse sweating and generalized body weakness. He also had myalgia and exertional dyspnoea; however, there was no lymphadenopathy, and the oral hygiene was good. All these symptoms were non-specific though the diagnosis of an infection or an inflammatory condition were most likely. He also had a travel history to the middle east; therefore, it is essential to consider such social factors in the diagnosis of HIV, although the prevalence of HIV in the middle east is relatively low .
Since clinical features are non-specific in HIV infection, blood investigations play a vital role in the diagnosis. The full blood count is an affordable, routinely performed test, even in resource-limited settings with essential clues for the diagnosis. Leucopenia is a common finding in HIV infection predominantly due to lymphopenia and neutropenia, and haemoglobin concentration is also low. The causes for these findings are multifactorial, including immune activation and release of cytokines, effects of antiretroviral therapy and opportunistic infections, which lead to decreased bone marrow production and increased peripheral destruction of cells . In our patient, the initial full blood count revealed a normal white cell count, 7.02 × 109 / L (4.09–11.00), and a normal neutrophil count, 6.67 × 109 / L (1.78–6.95). However, the lymphocyte count, 0.28 × 109 / L (1.34–3.92), and the eosinophil count, 0.01 × 109 / L (0.05–0.55), were low, along with a low haemoglobin level of 10.2 g/dL (13.4–16.7) .
ESR is not a helpful test in diagnosing HIV, although initially considered an indicator of disease progression, later studies disagreed or demonstrated only a negligible fall in CD4 count with rising ESR. At the same time, ESR does not predict acute illness in HIV, and when measured, it is not uncommon to discover values in triple figures in otherwise asymptomatic individuals with normal CD4 counts . However, HIV-infected individuals show a significant increase in CRP over time and the level of CRP is associated with HIV disease progression independent of CD4 lymphocyte count and HIV/RNA level . Our patient had a CRP level of 25 mg/L and an ESR of 80 mm/h, both values compatible with characteristic findings in HIV infection though not having any diagnostic value. Our patient also had hyponatremia with an average potassium level. Hyponatremia in HIV disease and AIDS occur in 20–80% of hospitalized patients. A syndrome of inappropriate ADH secretion, volume depletion, and adrenal insufficiency, as well as some drugs, are the most common causes of hyponatremia in HIV-infected patients .
HIV infection is confirmed either by detecting HIV-specific antibodies in serum or plasma or by demonstrating the presence of the virus by nucleic acid detection using polymerase chain reaction (PCR), p24 antigen testing or, rarely these days, by growing virus in cell culture. However, antibody testing is most commonly used to diagnose HIV infection . The most recent advances in EIA technology have produced ‘combination assays’, which allow for the simultaneous detection of p24 HIV antigen and HIV antibodies. This approach has further shortened the interval between HIV infection and detectable HIV antigen/antibodies . The diagnosis of HIV was made in our patient by Ag/Ab combo assay, where p24 antigen became positive. However, his CD4 count was 473 cells/mm3, lower than the standard value of 500–1200 cells/mm3. How it only when the CD4 count is less than 350 cells/mm3 it is considered as the risk for several infectious complications begins to rise, including varicella-zoster infection, severe bacterial infections and tuberculosis .
Fever in HIV patients is due to multiple factors. First, infection with HIV can cause fever, as is the case in 40–90% of patients with HIV primo-infection. Second, immunodeficiency in advanced HIV infection puts patients at high risk for opportunistic infections and malignancies . Therefore in a febrile patient with HIV, it is essential to investigate for opportunistic infections. A few common AIDS-defining opportunistic infections include tuberculosis, Candida infections, Pneumocystis pneumonia, Toxoplasma gondii encephalitis, and Cytomegalovirus retinitis . We investigated our patient for Cytomegalovirus, Toxoplasma, and Tuberculous infections, where all became negative. We also performed an HRCT chest to exclude Pneumocystis carinii infection, and it also turned out to be negative.
The WHO guidelines on HIV antiretroviral therapy revised recently in 2018. According to that, dolutegravir (DTG)-based regimen is recommended as the preferred first-line regimen for people living with HIV initiating antiretroviral therapy and DTG in combination with an optimized nucleoside reverse-transcriptase inhibitor backbone, which includes abacavir (ABC), emtricitabine (FTC), lamivudine (3TC) and zidovudine (AZT) is the preferred second-line regimen . However, according to the guideline published by the Ministry of Health, Sri Lanka in 2014, the first-line regimen for adult and adolescents includes the combination of tenofovir (TDF), 3TC (or FTC) and efavirenz (EFV) or AZT, 3TC and EFV . Therefore after the initial diagnosis of HIV, our patient was treated with EFV, FTC, and TDF, which is a standard first-line antiretroviral therapy in Sri Lanka. However, there was no evidence of pneumocystis infection; he was covered with meropenem, doxycycline and cotrimoxazole as prophylaxis.
There is an association between HIV infection and an increased likelihood of bacteraemia and mortality as a higher incidence of bacteraemia have been reported in immunocompromised patients. HIV-positive patients have been found to have an increased risk of non-typhoid salmonella bacteraemia with organisms Salmonella typhimurium and enteritidis compared to HIV-negative patients though the relationship between HIV and typhoid has been unclear [6, 22]. However, the diagnosis of typhoid should be considered in HIV infected individuals, mainly when they present with severe ulcerative diarrhoea. . The incidence of non-typhoid salmonellosis has been estimated to be 10 to 100 fold greater in HIV infected individuals compared to the general population . Nontyphoidal Salmonella bacteremia causes a significant public health problem and represents an important cause of morbidity and mortality in HIV-infected patients, representing around 10% of HIV infected individuals. Factors such as handwashing habit, contact with pet animals, consumption of raw or improperly cooked meat, milk, and vegetables have been indicated as potential sources of Salmonella infection . Thus recurrent Salmonella septicemia is considered an AIDS-defining illness .
Typhoid is an infectious disease that presents with non-specific symptoms. Patients complain of enterocolitis after 12 hours to 48 hours of inoculation. Often, they initially present with nausea, vomiting that progresses to diffuse abdominal pain, bloating, anorexia, and diarrhoea, which can vary from mild to severe diarrhoea with or without blood, followed by a short asymptomatic phase that gives way to bacteremia and fever with flu-like symptoms . Symptoms of enterocolitis generally last a few days and are self-limited without the need for medical intervention except in the old and very young. Immunocompromised patients with HIV, particularly those with low CD4 counts, more commonly present with severe diarrhoea and tend to have more metastatic severe infections . Classic typhoid fever follows a “step-ladder” pattern, and abdominal distress is frequently seen. Due to the hypertrophy of Payer patches, constipation may predominate over diarrhoea in some cases .
When typhoid is complicated by ileal perforation, tenderness, rigidity, and guarding of the abdomen may be present. Visible rose spots (rose-coloured macules on the abdomen) are associated with typhoid fever but rarely occur. The patient looks pale, mildly distressed, and dehydrated with sunken eyes, dry skin, and lethargy. Some patients have jaundice, pale stool, and dark urine when the patient has associated gallstones and other biliary pathology. Enlarged spleen on palpation may also be present . Our patient developed nausea, vomiting and diarrhoea after three days of antiretroviral therapy while continuing the preexisting fever followed by severe dyspnoea and epigastric pain in the following day associated with tachypnoea, tachycardia and hypotension. He also had preceding constipation. Therefore his clinical features were compatible with the characteristic features of enterocolitis and ileal perforation following typhoid fever. An urgent chest X-ray confirmed the bowel perforation by air under the diaphragm, where the surgical team found distal ileal perforation with a longitudinal white deep ulcer suggestive of a typhoid ulcer.
The approach to typhoid patients should be clinical. Patients residing in areas with poor sanitation or impure drinking water or a history of travel from endemic areas presenting with febrile illness for more than three days along with gastrointestinal manifestations (pain, constipation, or diarrhoea) are highly suspicious. Diagnosis in the first week is difficult, but various laboratory studies assist in making the diagnosis . However, the definitive diagnosis requires isolation of Salmonella typhi from blood, bone marrow, stool, or urine cultures . Other investigations such as the Widal test, skin snip test, polymerase chain reaction (PCR) assay and Enzyme-Linked Immunosorbent Assay (ELISA) test can also be done . However, since our patient presented with bowel perforation, there was no opportunity to perform these diagnostic tests. The histology of the resected specimen had findings suggestive of a perforated Typhoid ulcer. Ulcerations in typhoid generally occur in the terminal ileum, cecum and the ascending colon, and rarely in the left side of the colon . Overall, the histological picture of typhoid perforation was found to be one of chronic but discrete inflammation around the perforation site, with relatively mild-to-moderate mucosal changes. The pathogenesis of intestinal perforation in patients with typhoid fever is poorly understood concerning the host and bacterial factors involved. It is generally believed that perforation occurs in the Peyer patches of the distal ileum. Typhoid perforation has an inflammatory nature, showing that the inflammatory infiltrate consists predominantly of macrophages and T lymphocytes and that it is most severe in the deeper tissues .
Salmonella typhi infection in HIV/AIDS patients may cause life-threatening complications like septic shock, meningitis, and local abscess formation. They are severely ill are more prone to mortality. Disease severity may be affected by access to health care and treatment delays . Regarding risk factors for worse prognosis and complications of Salmonella infection, co-infections and acute renal failure are the most frequent, where the case fatality rate of typhoid significantly increase when present concurrently with HIV . Our patient developed severe pneumonia in the background of immunodeficiency in the postoperative period, where he scummed despite the resuscitation efforts. Though there was no aetiological diagnosis for pneumonia, he had been covered with broad-spectrum antibiotics. HIV patients with pulmonary infections requiring intensive care, Pneumocystis pneumonia and mechanical ventilation are associated with higher mortality. At the same time, not having an aetiological diagnosis is independently associated with higher mortality .