Clinical Meetings at RH Year 2001

2001 - A Missed Diagnosis- Treatable And Even Preventable

Dr. Kwok Yuk Lung, Dr Sin Kit Man

Case History
A 60-year-old housewife with good past health presented to a general practitioner in November 2000 complaining of insidious bilateral ankle edema and facial puffiness for a few weeks. She was born in Hong Kong with no recent travel history. She was hypertensive (BP 182/106 mmHg) with renal impairment (creatinine 223 umol/L), hyperlipidaemia and mild normochromic anaemia. Blood tests had been normal one year ago during a body check.

She was referred to the Renal Clinic of Tuen Mun Hospital and was seen in December 2000. Blood pressure was elevated and the level of renal impairment was similar. There was nephrotic range proteinuria 5.42g/day and creatinine clearance was 26 ml/minute. Antinuclear antibody was positive (centromere pattern, titre 1:80). Antineutrophil cytoplasmic antibody was also positive, and anti-myeloperoxidase antibody level was high (8.3%). Ultrasound scan of the kidneys was normal. The diagnoses were ANCA-positive glomerulonephritis with renal impairment, nephrotic syndrome, and renal hypertension. She was treated with Felodipine and Lasix. She was admitted to Tuen Mun Hospital in January 2001 for a transcutaneous fine needle renal biopsy. Proteinuria worsened to 11.64 g/day. The renal biopsy was uneventful. She was started on systemic steroid (Prednisolone lmg/kg/day) before discharge. The renal biopsy histology was consistent with membranous glomerulonephritis.

During the next month in the Renal Clinic she remained hypertensive with further impairment of creatinine clearance to 20 ml/minute. In view of the progressive renal failure, the renal physicians added oral cyclophosphamide lmg/kg/day since 14th February 2001. However, renal function test 2 weeks later showed no improvement (creatinine 252 umol/L).

She was admitted to the medical ward on 17th March 2001 complaining of exertional dyspnoea, fever, chills and rigor. CXR showed right lower zone patch of consolidation (Figure 1) while baseline CXR in January 2001 was normal. She was treated with 1 week's course of Ceftazidime. Steroid was continued while the cyclophosphamide was stopped. Fever resolved and the chest symptoms improved. However there was further deterioration of renal function in the next 10 days(creatinine 333--;>693 umol/L; creatinine clearance 8ml/minute). The clinical impression was progression to cresentic glomerulonephritis and she soon developed anuria before renal biopsy could be repeated and required peritoneal dialysis.



One day later she became hypotensive. There has been no change in her steroid doses and she remained afebrile. Peritoneal dialysis was withheld and intravenous fluid replaced. She passed tarry stool and this was supported with transfusion. The hypotension persisted and she eventually required inotropes infusion (dopamine and dobutamine) for blood pressure support. Her general state deteriorated with lethargy, vomiting and anorexia. She was further supported with parenteral nutritional. Dyspnoea recurred during this period of time. CXR showed diffuse bronchopneumonia in addition to the persistent right lower zone consolidation. (Figure 2) The creatinine level rose up to 912 umol/L.



She deteriorated further on ih April 2001 with desaturation despite high flow oxygen. lCU admission was sought but there was no bed available. She was intubated and mechanically ventilated under sedation (midazolam infusion). CXR showed rapid deterioration to bilateral diffuse dense consolidation (Figure 3).



The respirology team was consulted at this time and we took over the case and managed her in the High Dependency Unit. The differential diagnoses included uncontrolled bacterial or fungal pneumonia, Pneumocystis carinii pneumonitis, viral pneumonitis, autoimmune pneumonitis, massive pulmonary embolism and massive pulmonary haemorrhage. She was treated with broad-spectrum antibiotics (piperacillin/tazobactam, amikacin) together with intravenous gancyclovir and cotrimoxazole. Supportive treatment included inotropes infusion, peritoneal dialysis, parenteral nutrition, and optimization of mechanical ventilation. Hydrocortisone was continued since she has been on systemic steroid for 3 months and the haemodynamic state was unstable. Bronchoscopy via the endotracheal tube showed copious mucoid secretions arising from both lung bases, and there was patchy mucosal excoriations involving the lower lobes. There was no sign of pulmonary haemorrhage. No transbronchial biopsy was attempted as she was on positive pressure ventilation and in critical state. CXR after bronchoscopy showed rapid resolution of pneumonia shadows in multiple areas (Figure 4).



Bronchial aspirates obtained at right lower lobe were negative for leucocytes on microscopy. Bacterial culture grew methicillin-resistant Staphalococcus aureus and Acinetobacter species. There was also scanty growth of Candida albicans. Cytomegalovirus DEAFF test was positive in the bronchial aspirates but the specimens were negative for Pneumocystis carinii and acid-fast bacilli. All blood cultures were negative. Blood for CMV antigenaemia pp65 was positive for 24 cells/2x105 WBC. Echocardiogram showed normal left ventricle contractility and no evidence of acute pulmonary hypertension.

She developed swinging fever in the next few days and Vancomycin was added. However her general state continued to deteriorate with rapid radiological progression to adult respiratory distress syndrome (Figure 5), and cardiovascular collapse. She died 28 days after hospital admission.

The clinical course and fleeting radiological signs were not compatible with simple bacterial pneumonia. CMV pneumonitis was also not likely as the patient was all along lymphopenic (CMV pneumonitis typical occurs when an immunosuppressed patient recovers from lymphopenia), pp65 was in low level, and there was complete lack of response to gancyclovir treatment. The exact cause of the uncontrolled pneumonia and sepsis was uncertain and an autopsy examination was proposed. But it was refused by the relatives.

One day after the patient's death, the cytology report of the BAL fluids returned to be positive for filariform larvae of Strongyloides stercoralis. All differential white cell counts checked showed no eosinophilia even before the onset of her renal disease or administration of steroid. In retrospect the whole clinical and radiological picture was indeed typical of Strongyloides hyperinfection syndrome and we believed this is the final diagnosis. Since there was no suspicious of parasitic infestation before the patient's death, no stool or upper small bowel specimen has been obtained for analysis.



Discussion
Strongyloides stercoralis is one of the human intestinal nematodes1. Like other soil transmitted helminthes, it is endemic in areas with high humidity, warm temperature and poor sanitation. Human infection begins when the filariform larvae penetrates the skin. Characteristic cutaneous larva migrans may occur occasionally. The larvae travel through the venous system to the lungs, penetrate the alveolar wall, and ascend the tracheobronchial tree where they are swallowed. Maturation into adult worm occurs in the small bowel. Ova are deposited in the epithelium and soon hatch into the non-infective rhabditiform larvae so that eggs are usually not found in the stool. The rhabditiform larvae either go through the direct cycle to become the infective filariform larvae, or the indirect cycle to become adult worms which produce eggs outside the human body. Therefore Strongyloides is unique in having a free-living reservoir cycle apart from the parasitic life cycle. Only the female worms are present in the human.

Cellular immunity usually keeps the infestation under control. Yet some larvae still can transform into the infective form in the bowel, penetrate the mucosa, migrate and develop into adult worms. This low level of auto-infection enables the organism to persist for decades.

If cellular immunity is impaired, large proportion of rhabditiform larvae mature into the filariform larvae within the host. The increase in larval load causes dissemination and the hyperinfection syndrome. The single most important risk factor for hyperinfection is corticosteroid use.2 Apart from immunosuppression, steroid can mimic an endogenous parasite-derived regulatory hormone so that the female worm can produce more eggs3. Diabetes mellitus, haematological malignancy, chronic Strongyloides infection, renal failure, and gastric acid suppression4 are other contributing conditions. HIV5-6 and HTLV-17 infection are also known immunocompromised states that predispose to Strongyloides dissemination. Among all immunosuppressants, cyclosporin has activity against Strongyloidei; however the clinical significance is still unknown.

Strongyloides hyperinfection is uncommon, but certainly not rare. The prevalence was 10-20% in Africa, but was up to 85% in some under-developed areas9. In Hong Kong there was no epidemiological data concerning the exact prevalence of Strongyloides infection. One report states that the incidence on fecal examination is 0.1-0.3%10.In a 14-year period of time (1980-1994) in Queen Mary Hospital, there were only 35 documented cases of Strongyloides infection11. However the incidence of hyperinfection has increased in recent years, probably attributed to the wider use of immunosuppression therapy and HIV pandemic.

Most immunocompetent hosts are asymptomatic. Gastrointestinal manifestations are usually non-specific. Chest symptoms include cough, haemoptysis, wheezing, repeated pneumonia, or asthma symptoms that paradoxically worsen with corticosteroid use12. Larva curens (intermittent puritic eruption on the buttocks and trunk lasting several hours) is a characteristic dermatological sign, but most patients will develop non-specific urticaria, scratch marks below the umbilicus, or pruritus ani instead. Eosinophilia occurs in 25% of cases only13.

The clinical features of hyperinfection syndrome are equally variable. It can present as pneumonia or empyema in the chest or various acute and chronic abdominal manifestations. It can also produce features of CNS infection. Gram-negative septicaemia is usually associated as the bacteria are carried by the larvae when they penetrate the gut wall. Eosinophilia is typically absent. Diagnosis is seldom made early; up to 50% of cases are discovered at necropsy14. The reported mortality rate exceeds 80% even with appropriate anti-helminthic therapy13.

Radiological features are also diverse and variable 15,16.On the chest radiograph, early signs include miliary shadows, diffuse reticular interstitial opacities, patchy alveolar opacities, segmental or lobar opacities. In the advanced stage, there can be extensive airspace shadows affecting both lungs, with occasional pleural or pericardial effusion. Without treatment, ARDS quickly evolves. Rarely, ARDS develops after antihelminthic treatment due to release of toxic breakdown products 17.On the abdominal radiograph, there can be thickened mucosal folds, segmental small bowel dilatation or perforation. Among all these variable radiological features, a characteristic pattern of Strongyloides hyperinfection has been described by the radiologists of Hong Kong, which consist of fleeting and rapidly changing CXR signs, predominant small bowel abnormality on AXR, and close temporal relationship of CXR & AXR signsl8. Detection of larvae in stool or other specimens is difficult (Table 1). Serological diagnosis19 is an attractive alternative but it is not available in Hong Kong.



Thiabendazole is the best-studied agents against Strongyloides. The eradication rate is high (70-90%), but side effects are common (95%)20. Treatment failures and relapses do occur. Albendazole and ivermectin are newer agents with comparable efficacy and are better tolerated 21,22. However, all three agents are not marketed in Hong Kong. The only anti-helminthic agent available in Hong Kong is mebendazole. There is limited information about the efficacy against Strongyloides. The drug is poorly absorbed in the oral route and lacks effects on extra-intestinal parasites.

Strongyloides hyperinfection is theoretically preventable by screening. All patients with unexplained eosinophilia, prior to administration of systemic steroid, native to endemic areas, and co-existing high risk conditions should be screened.

References

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